TWI838626B - Lpa receptor antagonists and uses thereof - Google Patents

Abstract

The present disclosure relates generally to compounds that bind to Lysophosphatidic Acid Receptor 1 (LPAR1) and act as antagonists of LPAR1. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of LPAR1, including fibrosis and liver diseases such as non-alcoholic steatohepatitis (NASH), interstitial lung disease (ILD), or chronic kidney disease (CKD).

Description

LPA receptor antagonists and uses thereof

The present invention relates to compounds that bind to lysophosphatidic acid (LPA) receptors, such as LPAR1, and act as antagonists thereof. The present invention further relates to the use of such compounds for the treatment and/or prevention of diseases and/or conditions associated with one or more LPA receptors, for example, diseases or conditions associated with LPAR1.

Lysophosphatidic acid (mono-acyl-glycerol-3-phosphate, LPA) is a class of biologically active phospholipids that can be produced from lysophosphatidylcholine (LPC), for example, by the enzyme autotaxin. A typical LPA has glycerol, an ester-linked fatty acid at the sn-1 position, and a phosphate head group at the sn-3 position. LPAs with various fatty acids have been identified, including oleyl LPA (16:0), stearyl LPA (18:0), oleyl LPA (18:1), linoleyl LPA (18:2), and arachidonyl LPA (20:4). LPA exerts a wide range of cellular responses such as proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis through the rhodopsin G protein-coupled receptor (GPCR) family. Six LPA receptors have been characterized and found to differ in their tissue distribution and downstream signaling pathways. These six LPA receptors are often referred to interchangeably as LPAR1-6 (gene) or LPA1-6 (protein). LPA receptor-mediated signaling has been shown to affect many biological processes such as wound healing, immunity, carcinogenesis, angiogenesis, and neurogenesis.

In vivo studies involving LPA receptor-deficient mice or certain tool compounds have demonstrated the potential of LPA receptors as possible drug targets in various diseases, including cancer, fibrosis, inflammation, pain, and cardiovascular disease. In recent years, LPAR1 antagonists have been studied clinically in conjunction with fibrotic disease states, such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis.

There remains a need for LPA antagonists with desirable selectivity, potency, metabolic stability, or reduced adverse effects.

The present invention provides compounds useful as inhibitors of lysophosphatidic acid receptor 1 (LPAR1). The present invention further relates to the use of said compounds for treating and/or preventing diseases and/or conditions by binding to LPAR1 by said compounds.

In one embodiment, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen; C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered aryl; or a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl group is optionally substituted with 1 to 4 identical or different R ^1A , wherein each R ^1A is independently selected from halogen; cyano; nitro; pendoxy; C _1-4 alkyl; C _3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 R ^1B2 and R ^1B3 are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein each R ^1A alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 4 identical or different R ^1C , and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen or C _1-6 alkyl, and wherein each R ^1B1 , R ^1B2 and R ^1B3 alkyl and each R ^1B1 , R ^1B2 and R ^1B3 cycloalkyl are optionally substituted with 1 to 3 halogens; or R ¹ is -OR ^1D1 or -N(R ^1D1 )(R 1D2 ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein each C _1-6 alkyl or C _3-6 cycloalkyl is optionally substituted by 1 to 4 identical or different R ^1E , wherein each R ^1E is independently selected from halogen; cyano; hydroxyl; pendoxy; C _1-4 alkyl; C _3-10 cycloalkyl; 3 to 10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6 to 10 membered aryl; 5 to 10 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -OR ^1F1 ; -N(R ^1F1 )(R ^1F2 ); -C(O)N(R ^1F1 )(R ^1F2 ); -NR ^1F1 C(O)R ^1F2 ; -S(O) _0-2 R ^1F1 ; -S(O) ₂ N(R ^1F1 )(R ^1F2 ) and -NR ^1F1 S(O) ₂ R ^1F2 , wherein each R ^1F1 and R ^1F2 are independently hydrogen or C _1-6 alkyl, wherein each R ^1E alkyl, cycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 3 identical or different R ^1G , and wherein each R ^1G is independently C _1-4 alkyl, C _1-4 alkoxy, hydroxyl, halogen or cyano; R ² is hydrogen or C 1-4 alkoxy substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkoxy and C _3-10 cycloalkyl; or R ² is C _3-6 cycloalkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkoxy and _{C 1-6 alkyl; each R 3 is independently selected from deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl} ^, _{-OR 2A1} ^and -N(R ^2A1 )(R ^2A2 ), wherein the C _1-6 alkyl is optionally substituted with 1 to 3 identical or different substituents independently selected from C _1-4 alkoxy and halogen, and wherein each R ^2A1 and R ^2A2 are independently hydrogen or C _1-3 alkyl substituted with 1 to 3 identical or different halogens; n is 0, 1, 2, 3 or 4; R R ⁴ is C _1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkoxy, -C(O)N(R ^4A1 ) and -N(R ^4A1 )(R ^4A2 ), wherein each R ^4A1 and R ^4A2 are independently hydrogen, C _1-6 alkyl or C _3-10 cycloalkyl; or R ⁴ is C _3-6 cycloalkyl or a 3-6 membered heterocyclic group having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl or heterocyclic group is optionally substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkyl and C _1-4 alkoxy; X ¹ , X ² , X ³ and X ^each of ^Y1 and Y2 is independently selected from CH and N; each of Y1 and ^Y2 is independently hydrogen, deuterium, or _C1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from deuterium _, halogen, cyano, _C2-3 alkynyl, _C1-4 alkoxy and -C(O)NH-( _C1-4H3-9 ); and Z is _C1-8 alkyl; _C1-6 alkoxy; _C3-6 cycloalkyl; C a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the _alkyl , alkoxy, cycloalkyl, aryl, heterocyclic group or heteroaryl group is each optionally substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy and C _3-6 cycloalkyl, wherein the C _1-4 alkyl is optionally substituted with 1 to 3 identical or different substituents selected from C _1-4 alkoxy and halogen; or Y ¹ and Z together with the carbon to which they are attached form a C _3-6 cycloalkyl group; C a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the _cycloalkyl group, aryl group, heterocyclic group or heteroaryl group is each optionally substituted with 1 to 3 identical or different substituents independently selected from cyano, C _1-4 alkyl, C _1-4 alkoxy, C _6-10 aryl and halogen, wherein the C _1-4 alkyl group is optionally substituted with 1 to 3 identical or different substituents independently selected from C _1-4 alkoxy and halogen, and wherein the C _6-10 aryl group is optionally substituted with 1 to 3 identical or different substituents independently selected from C _1-4 alkyl, C _1-4 alkoxy and halogen, and Y ² is hydrogen or deuterium.

In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, R ¹ is hydrogen; C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _3-10 cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl; or 5-10 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted with 1 to 4 identical or different R ^1A , wherein each R ^1A is independently selected from halogen; cyano; nitro; pendoxy; C _1-4 alkyl; C _3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 , R ^1B2 and R ^1B3 are independently hydrogen or C _1-6 alkyl, wherein each R ^1A alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 4 identical or different R ^1C , and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), and wherein each R ^1D1 and R ^1D2 are independently hydrogen or C _1-6 alkyl; or R ¹ is -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein each C _1-6 alkyl or C 3-6 The _3-6 cycloalkyl group is optionally substituted by 1 to 4 identical or different R ^{1E groups} , wherein each R ^{1E group} is independently selected from halogen; cyano; hydroxyl; pendoxy; C _1-4 alkyl; C _3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered aryl group; a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -OR ^1F1 ; -N(R ^1F1 )(R ^1F2 ); -C(O)N(R ^1F1 )(R ^1F2 ); -NR ^1F1 C(O)R ^1F2 ; -S(O) _0-2 R ^1F1 ; -S(O) ₂ N(R ^1F1 )(R ^1F2 ) and -NR ^1F1 S(O) ₂ R ^1F2 , wherein each R ^1F1 and R ^1F2 are independently hydrogen or C _1-6 alkyl, wherein each R ^1E alkyl, cycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 3 identical or different R ^1G , and wherein each R ^1G is independently C _1-4 alkyl, C _1-4 alkoxy, hydroxyl, halogen or cyano; R ² is hydrogen or C 1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkoxy and C _3-10 cycloalkyl; or R ² is C _1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkoxy and C _1-6 alkyl; each R ³ is independently selected from deuterium, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, -OR ^2A1 and -N(R ^2A1 )(R ^2A2 ), wherein _{the C 1-6 alkyl} is optionally substituted with 1 to 3 identical or different substituents independently selected from C _1-4 alkoxy and halogen, and wherein each R ^2A1 and R ^2A2 is independently hydrogen or C _1-3 alkyl substituted with 1 to 3 identical or different halogens; n is 0, 1, 2, 3 or 4; R ⁴ is C 1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkoxy, -C(O)N(R ^4A1 ) and -N(R ^4A1 )(R ^4A2 ) wherein each of R ^4A1 and R ^4A2 is independently hydrogen, C _1-6 alkyl or C _3-10 cycloalkyl; or R ⁴ is C _3-6 cycloalkyl or a 3-6 membered heterocyclic group having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the _cycloalkyl or heterocyclic group is optionally substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkyl and C _1-4 alkoxy; each of X ¹ , X ² , X ³ and X ⁴ is independently selected from CH and N; each of Y ¹ and Y ² is independently hydrogen, deuterium, or optionally substituted with 1 to 3 identical or different substituents independently selected from deuterium, halogen, cyano, C _2-3 alkynyl, C 1-4 alkoxy; the alkyl radical being selected from the group consisting of -C(O)NH-(C _1-4 H _3-9 ) and -C _{1-6 alkyl radical being substituted with the same or different substituents selected from -C(O)NH-(C 1-4 H 3-9 ); and Z is a C 1-8 alkyl radical} ; a C _1-6 alkoxy radical; a C _3-6 cycloalkyl radical; a C _6-12 aryl radical; a 3- to 12-membered heterocyclic radical having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 12-membered heteroaryl radical having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the alkyl radical, alkoxy radical, cycloalkyl radical, aryl radical, heterocyclic radical or heteroaryl radical is each optionally substituted with the same or different substituents selected independently from halogen, cyano, C _1-4 alkyl radical, C _1-4 alkoxy radical and C _3-6 cycloalkyl radical, wherein the C _1-4 alkyl radical is optionally substituted with 1 to 3 heteroatoms selected from C 6-12 or ^Y1 and Z together with the carbon to which they are attached form a _C3-6 cycloalkyl group; a _C6-12 aryl group; a 3-12 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or _{a 5-12} membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl group, aryl group, heterocyclic group or heteroaryl group is each optionally substituted with 1 to 3 same or different substituents independently selected from cyano, _C1-4 alkyl, _C1-4 alkoxy, _C6-10 aryl and halogen, wherein the C1-4 alkyl group is optionally substituted with 1 to 3 same or different substituents independently selected from C1-4 alkoxy and halogen, and wherein the _C1-4 alkyl group is optionally substituted with 1 to 3 same or different substituents independently selected from _C1-4 alkoxy and halogen, and wherein the C _{The 6-10} aryl group is optionally substituted with 1 to 3 identical or different substituents independently selected from C _1-4 alkyl, C _1-4 alkoxy and halogen, and Y ² is hydrogen or deuterium.

In some embodiments, provided herein are pharmaceutical compositions comprising a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.

In some embodiments, the present invention provides a method of inhibiting LPAR1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

In some embodiments, the present invention provides a method for treating a patient suffering from an LPAR1-mediated condition, comprising administering to the patient a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

Cross-reference to related applications

This application claims the benefit of 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/034,220, filed on June 3, 2020, and U.S. Provisional Application No. 63/130,242, filed on December 23, 2020, which are hereby incorporated by reference in their entirety for all purposes.

The present invention relates to LPA receptor antagonists, such as antagonists of LPAR1. The present invention also relates to compositions and methods related to LPAR1 antagonists and the use of such compounds for treating and/or preventing LPAR1-mediated diseases and conditions. The present invention also relates to compositions and methods for treating and/or preventing liver disease, including LPAR1 antagonists and one or more additional therapeutic agents.

It is generally believed that patients with certain LPAR1-mediated diseases, such as cancer, fibrosis, inflammation, pain, and cardiovascular disease or liver disease, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), may benefit from treatment with LPAR1 antagonists and, optionally, one or more additional therapeutic agents.

The following description is made with the understanding that the present invention is considered an example of the claimed subject matter and is not intended to limit the scope of the appended patent application to the specific embodiments described. The headings used throughout the present invention are provided for convenience and are not to be considered to limit the scope of the patent application in any way. The embodiments described under any heading may be combined with the embodiments described under any other heading.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. It should be noted that the singular forms "a", "an" and "the" used herein and in the appended claims include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art, etc.

As used in this specification, the following terms and phrases are generally intended to have the meanings as set forth below, except where the context in which they are used indicates otherwise.

A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, _-CONH2 is attached through a carbon atom. A dash at the beginning or end of a chemical group is for convenience; a chemical group can be depicted with or without one or more dashes without losing its ordinary meaning. A wavy line drawn through the line in the structure indicates the point of attachment of the group. Unless required chemically or structurally, the order in which the chemical groups are written or named does not indicate or imply directionality. A solid line from the center of a ring indicates that the point of attachment of a substituent on the ring can be at any ring atom. For example, ^Ra in the following structure can be attached to any of the five carbon ring atoms, or ^Ra can replace a hydrogen attached to a nitrogen ring atom: .

The prefix " _Cuv " indicates that the following group has u to v carbon atoms. For example, " _C1-6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms. Similarly, the term "x to y membered" ring (where x and y are numerical ranges, such as "3 to 12 membered heterocyclic group") refers to a ring containing xy (e.g., 3-12) atoms, up to 80% of which may be heteroatoms such as N, O, S, P, and the remaining atoms are carbon.

In addition, some commonly used alternative chemical names may or may not be used. For example, divalent groups such as divalent "alkyl" and divalent "aryl" may also be referred to as "alkylene" or "alkylenyl" or alkylyl, "arylene" or "arylenyl" or arylyl, respectively.

"Compounds disclosed herein" or "compounds of the present invention" or "compounds provided herein" or "compounds described herein" refer to compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi). Also included are specific compounds 1 to 338 provided above (e.g., Examples 1-92).

Herein, references to "about" a value or parameter include (and describe) embodiments for the value or parameter itself. In certain embodiments, the term "about" includes an indicated amount ±10%. In other embodiments, the term "about" includes an indicated amount ±5%. In certain other embodiments, the term "about" includes an indicated amount ±1%. In addition, the term "about X" includes a description of "X". In addition, unless the context clearly indicates otherwise, the singular forms "a" and "the" include plural references. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "analytical methods" includes reference to one or more analytical methods and their equivalents known to those skilled in the art.

"Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., _C1-20 alkyl), 1 to 8 carbon atoms (i.e., _C1-8 alkyl), 1 to 6 carbon atoms (i.e., _C1-6 alkyl), 1 to 4 carbon atoms (i.e., _C1-4 alkyl), or 1 to 3 carbon atoms (i.e., _C1-3 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, dibutyl, isobutyl, tertiary butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a particular number of carbons is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons are encompassed; thus, for example, "butyl" includes n-butyl (i.e., -( _CH2 ) _3CH3 ), dibutyl (i.e., -CH( _CH3 ) _CH2CH3 ), isobutyl (i.e., _-CH2CH ( _CH3 ) ₂ ), and _tertiary butyl ( _i.e. , -C( _CH3 ) ₃ ); and "propyl" includes n-propyl (i.e., -( _CH2 ) _2CH3 ) and isopropyl (i.e., -CH( _CH3 ) _{2 )} .

"Alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., _C2-20 alkenyl), 2 to 8 carbon atoms (i.e., _C2-8 alkenyl), 2 to 6 carbon atoms (i.e., _C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., _C2-4 alkenyl). Examples of alkenyl include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

"Alkynyl" refers to an aliphatic group containing at least one carbon-carbon carbon bond and having 2 to 20 carbon atoms (i.e., _C2-20 alkynyl), 2 to 8 carbon atoms (i.e., _C2-8 alkynyl), 2 to 6 carbon atoms (i.e., _C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., _C2-4 alkynyl). The term "alkynyl" also includes those groups having one carbon bond and one double bond.

"Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, di-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

"Acyl" refers to the radical -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclo, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

"Aminyl" refers to the group ^-NRyRz , wherein ^{Ry and Rz} are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclo; each of which may be optionally substituted.

"Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, an aryl group has 6 to 20 ring carbon atoms (i.e., _C6-20 aryl), 6 to 12 carbon ring atoms (i.e., _C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., _C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is a heteroaryl group.

"Cyano" or "carbonitrile" refers to the radical -CN.

"Cycloalkyl" refers to saturated or partially saturated cycloalkyl groups having a single ring or multiple rings, including fused, bridged and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 ring carbon atoms (i.e., _C3-20 cycloalkyl groups), 3 to 12 ring carbon atoms (i.e., _C3-12 cycloalkyl groups), 3 to 10 ring carbon atoms (i.e., _C3-10 cycloalkyl groups), 3 to 8 ring carbon atoms (i.e., _C3-8 cycloalkyl groups), or 3 to 6 ring carbon atoms (i.e., _C3-6 cycloalkyl groups). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

"Fused" means that the ring is bonded to an adjacent ring. In some embodiments, the fused ring system is a heterocyclic ring. In some embodiments, the fused ring system is an oxahertabicyclohexane. In some embodiments, the fused ring system is .

"Bridged" refers to a ring fusion in which non-adjacent atoms on the ring are joined by a divalent substituent (e.g., alkylene, alkylene containing one or two heteroatoms) or a single heteroatom. Quininyl and adamantyl are examples of bridged ring systems. In some embodiments, the bridged ring is dicyclopentyl (bicyclo[1.1.1]pentyl]) or bicyclooctyl (bicyclo[2.2.2]octyl). In some embodiments, the bridged ring is .

"Spiro" refers to a cyclo substituent joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxacyclopentane, and 4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine are spiro substituents, respectively. In some embodiments, the spiro substituent is spiropentyl (spiro[ab]pentyl), spirohexenyl, spiroheptyl, or spirodecanyl. In some embodiments, the spiro substituent is .

"Halogen" or "halogen group" includes fluorine, chlorine, bromine and iodine.

"Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more heteroaryl atoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., _C1-20 heteroaryl), 3 to 12 carbon ring atoms (i.e., _C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., _C3-8 heteroaryl); and 1 to 5 heteroaryl atoms, 1 to 4 heteroaryl atoms, 1 to 3 heteroaryl atoms, 1 to 2 heteroaryl atoms, or 1 heteroaryl atom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridinyl, pyridinyl, benzothiazolyl and pyrazolyl. Heteroaryl groups do not include aryl groups as defined above or overlap with them.

"Heterocyclic" or "heterocyclic ring/heterocycle" refers to a non-aromatic cycloalkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, unless otherwise indicated, "heterocyclic" or "heterocyclic ring/heterocycle" refers to a saturated or partially saturated ring, for example, in some embodiments, "heterocyclic" or "heterocyclic ring/heterocycle" refers to a partially saturated ring in a specific instance. The term "heterocyclic" or "heterocyclic ring/heterocycle" includes heterocycloalkenyl (i.e., a heterocyclic group having at least one double bond). A heterocyclic group may be a single ring or multiple rings, wherein the multiple rings may be fused, bridged or spiro-connected. As used herein, a heterocyclic group has 2 to 20 carbon ring atoms (i.e., _C2-20 heterocyclic group), 2 to 12 carbon ring atoms (i.e., _C2-12 heterocyclic group), 2 to 10 carbon ring atoms (i.e., _C2-10 heterocyclic group), 2 to 8 carbon ring atoms (i.e., _C2-8 heterocyclic group), 3 to 12 carbon ring atoms (i.e., _C3-12 heterocyclic group), 3 to 8 carbon ring atoms (i.e., _C3-8 heterocyclic group) or 3 to 6 carbon ring atoms (i.e., C _3-6 heterocyclic ring); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatoms independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperonyl, oxetanyl, dioxolanyl, azanyl and linolyl. As used herein, the terms "heterocycle" and "heterocyclic ring" and "heterocyclyl" are used interchangeably.

"Hydroxy" or "hydroxyl" refers to the group -OH.

"Oxy" refers to the group (=O) or (O).

"Sulfonyl" refers to the radical -S(O) _2Rc , ^{wherein Rc} is alkyl, heterocyclic, cycloalkyl, heteroaryl or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

Unless otherwise indicated, whenever a graphic representation of a group terminates in a single bond to a nitrogen atom, that group represents a -NH ₂ group. Similarly, unless otherwise indicated, the presence of hydrogen atoms where necessary to complete the valence or provide stability is meant and assumed, taking into account the knowledge of those skilled in the art.

The term "optionally" or "as the case may be" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. In addition, the term "optionally substituted" means that any one or more hydrogen atoms on the designated atom or group may or may not be replaced with a moiety other than hydrogen.

The term "substituted" means that any one or more hydrogen atoms on the designated atom or group are replaced by one or more substituents other than hydrogen, with the proviso that the normal valence of the designated atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amine, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halogen, halogenalkyl, halogenoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazine, imino, pendoxy, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or a combination thereof. Polymers or similar infinite structures obtained by defining substituents with unlimited additional substituents (e.g., substituted aryl with substituted alkyl, which is itself substituted by substituted aryl, which is further substituted by substituted heteroalkyl, etc.) are not intended to be included herein. Unless otherwise indicated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl with two other substituted aryls is limited to aryl substituted with (aryl substituted with (substituted aryl)). Similarly, the above definition is not intended to include disallowed substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl with two adjacent oxygen ring atoms). Such disallowed substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups as defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl." Unless otherwise specified, where a group is described as optionally substituted, any substituent of that group is itself unsubstituted.

In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxyl, halogen, amino, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl. In additional embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents including alkyl, halogen, cycloalkyl, heterocyclic, aryl, heteroaryl, amino, alkoxy, halogen, pendoxy, and hydroxyl; "substituted heterocyclic" refers to a heterocyclic group having one or more substituents including alkyl, amino, halogen, heterocyclic, cycloalkyl, aryl, heteroaryl, alkoxy, halogen, pendoxy, and hydroxyl. ; "substituted aryl" refers to aryl having one or more substituents including halogen, alkyl, amino, haloalkyl, cycloalkyl, heterocyclic, heteroaryl, alkoxy and cyano; "substituted heteroaryl" refers to heteroaryl having one or more substituents including halogen, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkoxy and cyano; and "substituted sulfonyl" refers to the group -S(O) _2R , wherein R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halogen, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which is unsubstituted.

In some embodiments, substituted cycloalkyl, substituted heterocyclo, substituted aryl and/or substituted heteroaryl include cycloalkyl, heterocyclo, aryl and/or heteroaryl groups having substituents on the ring atoms that connect the cycloalkyl, heterocyclo, aryl and/or heteroaryl group to the rest of the compound. For example, in the following moiety, the cyclopropyl group is substituted with a methyl group: .

The disclosure illustratively described herein may be properly practiced without any one or more elements, one or more limitations not specifically disclosed herein. Thus, for example, the terms "comprising", "including", "containing", etc. should be understood broadly and non-restrictively. Furthermore, the terms and expressions employed are used as terms of description rather than limitation, and in the use of such terms and expressions, no equivalents or portions thereof of the features shown and described are intended to be excluded, but it should be recognized that various modifications are possible within the scope of the invention.

The compounds of the present invention may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids (including inorganic bases or acids and organic bases or acids). The compounds of the present invention may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids (including inorganic bases or acids and organic bases or acids). If the compounds of the present invention contain one or more acid groups or alkaline groups, the present invention also includes the corresponding pharmaceutically or toxicologically acceptable salts, specifically, their pharmaceutically usable salts. Thus, compounds according to the invention containing acid groups may be present on these groups and may be used according to the invention, for example, as alkaline metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine, amino acids or other bases known to those skilled in the art. Compounds according to the invention containing one or more alkaline groups (i.e. groups that can be protonated) may be present and may be used according to the invention in the form of addition salts thereof with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfuric acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, apple acid, aminosulfuric acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and others known to those skilled in the art.

If the compounds of the invention contain both acidic and alkaline groups in the molecule, the invention also includes internal salts or betaines (amphoteric ions) in addition to the salt forms mentioned. The respective salts can be obtained by customary methods known to those skilled in the art, for example by contacting these with organic or inorganic acids or bases in a solvent or dispersion, or by anion exchange or cation exchange with other salts.

The present invention also includes all salts of the compounds of the present invention which are not directly suitable for use in pharmaceuticals due to low physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. Acids and bases suitable for reacting with the base compound to form pharmaceutically acceptable salts (acid addition or base addition salts, respectively) are known to those skilled in the art. Similarly, methods for preparing pharmaceutically acceptable salts from the base compound (disclosed above) are known to those skilled in the art and are disclosed, for example, in Berge et al. Journal of Pharmaceutical Science, Vol. 66, No. 1, January 1977, and other sources.

In addition, the compounds disclosed herein may undergo tautomerism. Where tautomerism of a compound or a prodrug thereof may occur, such as keto-enol tautomerism, each of the individual forms, such as, for example, the keto and enol forms, as well as mixtures thereof in any ratio, are within the scope of the present invention. The same applies to stereoisomers, such as, for example, enantiomers, cis/trans isomers, diastereomers, conformational isomers, and the like.

The term "protecting group" refers to a moiety in a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See, e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often used to mask the reactivity of certain functional groups to aid the efficiency of a desired chemical reaction, e.g., to form and break chemical bonds in an orderly and planned manner. The term "deprotection" refers to the removal of a protecting group.

Those skilled in the art will appreciate that when a list of alternative substituents includes members thereof that cannot be substituted for a particular group due to their valence requirements or other reasons, the list is intended to be understood by those skilled in the art to include only those members of the list that are suitable for substitution for the particular group.

In addition, the compounds of the present invention may exist in the form of a solvent complex, such as those comprising water or a pharmaceutically acceptable solvent complex (such as alcohol, in particular, ethanol). A "solvent complex" is formed by the interaction of a solvent and a compound.

In certain embodiments, optical isomers, racemates, or other mixtures thereof of the compounds described herein or pharmaceutically acceptable salts or mixtures thereof are provided. If desired, isomers can be separated by methods well known in the art, such as by liquid chromatography. In such cases, single enantiomers or diastereomers (i.e., optically active forms) can be obtained by asymmetric synthesis or by resolution. Resolution can be achieved, for example, by known methods, such as crystallization in the presence of an analytical agent, or chromatography using, for example, a chiral high pressure liquid chromatography (HPLC) column.

"Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but with different three-dimensional structures that are not interchangeable. The present invention encompasses various stereoisomers and mixtures thereof and includes "enantiomers", which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

In some embodiments, the compounds disclosed herein and their pharmaceutically acceptable salts may include asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms of amino acids that can be defined in terms of absolute stereochemistry as (R)- or (S)- or (D)- or (L)-. The embodiments therefore include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using known techniques such as chromatography and fractional crystallization. Known techniques for preparing/isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

The compositions provided herein including the compounds described herein or pharmaceutically acceptable salts thereof, isomers or mixtures thereof may include racemic mixtures or mixtures containing an enantiomeric excess of one enantiomer or a single diastereomer or a mixture of diastereomers. All such isomeric forms of these compounds are expressly included herein, as if each isomeric form were specifically and individually listed.

Any formula or structure given herein is also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms. Isotopically labeled compounds have structures depicted by the chemical formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, ² H (deuterium, D), ³ H (tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, and ¹²⁵ I. Various isotopically labeled compounds of the present invention are, for example, those into which radioactive isotopes such as ³ H, ¹³ C, and ¹⁴ C are incorporated. These isotopically labeled compounds may be useful in metabolic studies; reaction kinetic studies; detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including analysis of drug or substrate tissue distribution; or for radiotherapy of patients. Isotopically labeled compounds and prodrugs thereof of the present invention may generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below, by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

The present invention also includes "deuterated analogs" of the compounds disclosed herein, in which 1 to n hydrogens attached to a carbon atom are replaced with deuterium, wherein n is the number of hydrogens in the molecule. Such compounds exhibit increased metabolic resistance and are therefore useful for increasing the half-life of any compound of Formula I when administered to mammals (e.g., humans). See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced with deuterium.

Deuterium-labeled or substituted therapeutic compounds of the present invention may have beneficial drug metabolism and pharmacokinetic (DMPK) properties, which are related to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements and/or improved therapeutic index. ¹⁸ F-labeled compounds may be suitable for PET or SPECT studies.

The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present invention, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," it is understood that the position has hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present invention, any atom specifically designated as deuterium (D) is intended to represent deuterium.

In addition, the present invention provides a pharmaceutical composition comprising the compound of the present invention, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvent thereof together with a pharmaceutically acceptable carrier as an active ingredient.

"Pharmaceutical composition" means one or more active ingredients and one or more inert ingredients constituting a carrier, as well as any product directly or indirectly produced by the combination, complex or aggregation of any two or more ingredients, or by the dissociation of one or more ingredients, or by other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical composition of the present invention can cover any composition prepared by blending at least one compound of the present invention with a pharmaceutically acceptable carrier.

As used herein, "pharmaceutically acceptable carriers" include excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents and the like, which are not harmful to the compounds of the present invention or their use. The use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (G.S. Banker & C.T. Rhodes, eds.).

" _IC50 " or " _EC50 " refers to the inhibitory concentration required to achieve 50% of the maximal desired effect. In many cases herein, the maximal desired effect is inhibition of LPA-induced LPAR1 activation. This term is obtained using in vitro assays (such as calcium mobilization assays) to assess concentration-dependent inhibition of LPA-induced LPAR1 activity.

"Treatment" is an approach used to obtain beneficial or desired results (including clinical results). Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and/or reducing the severity of the disease or condition); b) slowing or halting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the onset of the disease or condition); and/or c) alleviate the disease, i.e., resolve clinical symptoms (e.g., improve disease symptoms, provide partial or total relief from the disease or condition, enhance the effect of another drug therapy, delay the progression of the disease, improve quality of life, and/or prolong survival). In some embodiments, the term "treatment" or "treating" means administering a compound or a pharmaceutically acceptable salt of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi) for the purpose of: (i) delaying the onset of a disease, i.e., preventing or delaying the development of clinical symptoms of a disease; (ii) inhibiting a disease, i.e., stopping the development of clinical symptoms; and/or (iii) alleviating a disease, i.e., causing a regression of clinical symptoms or their severity.

"Prevention" or "preventing" means any treatment of a disease or condition that prevents the clinical symptoms of the disease or condition from developing. In some embodiments, the compound can be administered to an individual (including a human) who is at risk for the disease or condition or has a family history of the disease or condition.

"Subject" refers to an animal that has been or will be the subject of treatment, observation, or experiment, such as a mammal (including a human). The methods described herein can be applied to human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof, means an amount sufficient to effect treatment to provide a therapeutic benefit (such as improving symptoms or slowing disease progression) when administered to a subject. For example, a therapeutically effective amount may be an amount sufficient to reduce symptoms of a disease or condition responsive to an LPAR1 antagonist. The therapeutically effective amount may vary depending on the subject and the disease or condition to be treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, which can be readily determined by one or ordinary skill. List of Abbreviations and Acronyms Abbreviation Meaning ACN or MeCN Acetonitrile aq. Water-based Bn Benzyl COPD Chronic obstructive pulmonary disease DCM Dichloromethane DIEA N,N-Diisopropylethylamine DMF N,N -Dimethylformamide DMSO Dimethyl sulfoxide DPPA Diphenylphosphinoyl azide EA Ethyl acetate EDTA Ethylenediaminetetraacetic acid ESI Electrospray Ionization Et Ethyl _Et2O Diethyl ether EtOAc Ethyl acetate H or hr(s) Hours HBSS Hanks' Balanced Salt solution HCC Hepatocellular carcinoma HPLC HPLC LCMS or LC/MS Liquid chromatography-mass spectrometry LPA Lysophosphatidic acid LPC Lysophospholipid acylcholine Me methyl MeOH Methanol MS Mass Spectrometry m/z Mass-to-charge ratio NADPH DAC NAFLD Nonalcoholic fatty liver disease NASH Nonalcoholic steatohepatitis NMR NMR spectroscopy PBC Primary biliary cirrhosis PE Petroleum ether PSC Primary sclerosing cholangitis rpm RPM RT or rt Room temperature sat. Saturation TEMPO 2,2,6,6-Tetramethylpiperidinyl 1-oxyl TFA Trifluoroacetate THF Tetrahydrofuran T3P Propane phosphoric anhydride

As used herein, "LPAR1 antagonist" refers to any agent that is capable of binding to and inhibiting LPAR1. LPAR1 (also known as LPA ₁ ) is a GPCR that binds the lipid signaling molecule lysophosphatidic acid (LPA). Exemplary reference sequences for LPAR1 include NCBI reference sequences NP_001392 (human protein), NP_001277415 (mouse protein), NM_001401 (human mRNA), and NM_001290486 (mouse mRNA). LPAR1 antagonists can be used as competitive inhibitors of all or part of LPAR1 agonists, or as inverse agonists. The activity of LPAR antagonists can be measured by methods known in the art, such as those described and cited in Castelino et al., 2010 Arthritis Rheum. 2011 May;63(5):1405-1415 or Swaney et al., J Pharmacol Exp Ther. 2011 Mar;336(3):693-700.

As used herein, "ACC inhibitor" refers to any reagent that is capable of binding to and inhibiting acetyl-CoA carboxylase (ACC). ACC inhibitors can be used as inhibitors or partial inhibitors of ACC. The reagent can be a compound or a biomolecule (e.g., a protein or an antibody). The activity of an ACC inhibitor can be measured by methods known in the art, such as those described and cited in U.S. Patent No. 8,969,557 and/or U.S. Patent No. 10,208,063, which are incorporated herein by reference in their entirety.

As referred to herein, an "ASK1 inhibitor" can be any reagent that is capable of inactivating the apoptosis signal-regulating kinase 1 (ASK1) protein. The reagent can be a compound or a biomolecule (e.g., a protein or an antibody). The activity of the ASK1 protein can be measured by several different methods. For example, the activity of the ASK1 protein can be determined based on the ability of the ASK1 protein to phosphorylate a substrate protein. Methods for identifying ASK1 inhibitors are known (see, e.g., U.S. 2007/0276050). Exemplary ASK1 substrate proteins include MAPKK3, MAPKK4, MAPKK6, MAPKK7, or fragments thereof. ASK1 protein activity can also be measured by the phosphorylation level of the ASK1 protein, such as the phosphorylation amount of the threonine residue in the ASK1 protein corresponding to threonine 838 (T838) of the human full-length ASK1 protein or threonine 845 (T845) of the mouse full-length ASK1 protein. For example, in the case where the ASK1 protein comprises the full-length human ASK1 protein sequence, the ASK1 inhibitor can attenuate the phosphorylation of T838 in the full-length human ASK1 protein sequence. Site-specific antibodies against human ASK1 T838 or mouse ASK1 T845 can be used to detect the phosphorylation level.

As used herein, "FXR agonist" refers to any agent that is capable of binding to and activating a farnesoid X receptor (FXR), which may be referred to as a bile acid receptor (BAR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4) receptor. An FXR agonist may be used as an agonist or partial agonist of FXR. An agent may be a compound or a biomolecule (e.g., a protein or an antibody). The activity of an FXR agonist may be measured by several different methods, such as in an in vitro assay using a fluorescence resonance energy transfer (FRET) cell-free assay, as described in Pellicciari et al., Journal of Medicinal Chemistry, 2002 Vol. 15, No. 45:3569-72. Compounds

In one embodiment, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen; C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered aryl; or a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl group is optionally substituted with 1 to 4 identical or different R ^1A , wherein each R ^1A is independently selected from halogen; cyano; nitro; pendoxy; C _1-4 alkyl; C _3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 R ^1B2 and R ^1B3 are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein each R ^1A alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 4 identical or different R ^1C , and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen or C _1-6 alkyl, and wherein each R ^1B1 , R ^1B2 and R ^1B3 alkyl and each R ^1B1 , R ^1B2 and R ^1B3 cycloalkyl are optionally substituted with 1 to 3 halogens, or R ¹ is -OR ^1D1 or -N(R ^1D1 )(R 1D2 ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein each C _1-6 alkyl or C _3-6 cycloalkyl is optionally substituted by 1 to 4 identical or different R ^1E , wherein each R ^1E is independently selected from halogen; cyano; hydroxyl; pendoxy; C _1-4 alkyl; C _3-10 cycloalkyl; 3 to 10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6 to 10 membered aryl; 5 to 10 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -OR ^1F1 ; -N(R ^1F1 )(R ^1F2 ); -C(O)N(R ^1F1 )(R ^1F2 ); -NR ^1F1 C(O)R ^1F2 ; -S(O) _0-2 R ^1F1 ; -S(O) ₂ N(R ^1F1 )(R ^1F2 ) and -NR ^1F1 S(O) ₂ R ^1F2 , wherein each R ^1F1 and R ^1F2 are independently hydrogen or C _1-6 alkyl, wherein each R ^1E alkyl, cycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 3 identical or different R ^1G , and wherein each R ^1G is independently C _1-4 alkyl, C _1-4 alkoxy, hydroxyl, halogen or cyano; R ² is hydrogen or C 1-4 alkoxy substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkoxy and C _3-10 cycloalkyl; or R ² is C _3-6 cycloalkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkoxy and _{C 1-6 alkyl; each R 3 is independently selected from deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl} ^, _{-OR 2A1} ^and -N(R ^2A1 )(R ^2A2 ), wherein the C _1-6 alkyl is optionally substituted with 1 to 3 identical or different substituents independently selected from C _1-4 alkoxy and halogen, and wherein each R ^2A1 and R ^2A2 are independently hydrogen or C _1-3 alkyl substituted with 1 to 3 identical or different halogens; n is 0, 1, 2, 3 or 4; R R ⁴ is C _1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkoxy, -C(O)N(R ^4A1 ) and -N(R ^4A1 )(R ^4A2 ), wherein each R ^4A1 and R ^4A2 are independently hydrogen, C _1-6 alkyl or C _3-10 cycloalkyl; or R ⁴ is C _3-6 cycloalkyl or a 3-6 membered heterocyclic group having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl or heterocyclic group is optionally substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkyl and C _1-4 alkoxy; X ¹ , X ² , X ³ and X ^each of ^Y1 and Y2 is independently selected from CH and N; each of Y1 and ^Y2 is independently hydrogen, deuterium, or _C1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from deuterium _, halogen, cyano, _C2-3 alkynyl, _C1-4 alkoxy and -C(O)NH-( _C1-4H3-9 ); and Z is _C1-8 alkyl; _C1-6 alkoxy; _C3-6 cycloalkyl; C a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the _alkyl , alkoxy, cycloalkyl, aryl, heterocyclic group or heteroaryl group is each optionally substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy and C _3-6 cycloalkyl, wherein the C _1-4 alkyl is optionally substituted with 1 to 3 identical or different substituents selected from C _1-4 alkoxy and halogen; or Y ¹ and Z together with the carbon to which they are attached form a C _3-6 cycloalkyl group; C a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the _cycloalkyl group, aryl group, heterocyclic group or heteroaryl group is each optionally substituted with 1 to 3 identical or different substituents independently selected from cyano, C _1-4 alkyl, C _1-4 alkoxy, C _6-10 aryl and halogen, wherein the C _1-4 alkyl group is optionally substituted with 1 to 3 identical or different substituents independently selected from C _1-4 alkoxy and halogen, and wherein the C _6-10 aryl group is optionally substituted with 1 to 3 identical or different substituents independently selected from C _1-4 alkyl, C _1-4 alkoxy and halogen, and Y ² is hydrogen or deuterium.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R ¹ is hydrogen; C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _3-10 cycloalkyl; 3 to 10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6 to 10 membered aryl; or 5 to 10 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted with 1 to 4 identical or different R ^1A , wherein each R ^1A is independently selected from halogen; cyano; pendoxy; C _1-4 alkyl; C _3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 , R ^1B2 and R ^1B3 are independently hydrogen or C _1-6 alkyl, wherein each R ^1A alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 4 identical or different R ^1C , and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen or C _1-6 alkyl; or R ¹ is -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein each C _1-6 alkyl or C 3-6 The _3-6 cycloalkyl group is optionally substituted by 1 to 4 identical or different R ^{1E groups} , wherein each R ^{1E group} is independently selected from halogen; cyano; hydroxyl; pendoxy; C _1-4 alkyl; C _3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered aryl group; a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -OR ^1F1 ; -N(R ^1F1 )(R ^1F2 ); -C(O)N(R ^1F1 )(R ^1F2 ); -NR ^1F1 C(O)R ^1F2 ; -S(O) _0-2 R ^1F1 ; -S(O) ₂ N(R ^1F1 )(R ^1F2 ) and -NR ^1F1 S(O) ₂ R ^1F2 , wherein each R ^1F1 and R ^1F2 are independently hydrogen or C _1-6 alkyl, wherein each R ^1E alkyl, cycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 3 identical or different R ^1G , and wherein each R ^1G is independently C _1-4 alkyl, C _1-4 alkoxy, hydroxyl, halogen or cyano; R ² is hydrogen or C 1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkoxy and C _3-10 cycloalkyl; or R ² is C _1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkoxy and C _1-6 alkyl; each R ³ is independently selected from deuterium, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, -OR ^2A1 and -N(R ^2A1 )(R ^2A2 ), wherein _{the C 1-6 alkyl} is optionally substituted with 1 to 3 identical or different substituents independently selected from C _1-4 alkoxy and halogen, and wherein each R ^2A1 and R ^2A2 is independently hydrogen or C _1-3 alkyl substituted with 1 to 3 identical or different halogens; n is 0, 1, 2, 3 or 4; R ⁴ is C 1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkoxy, -C(O)N(R ^4A1 ) and -N(R ^4A1 )(R ^4A2 ) wherein each of R ^4A1 and R ^4A2 is independently hydrogen, C _1-6 alkyl or C _3-10 cycloalkyl; or R ⁴ is C _3-6 cycloalkyl or a 3-6 membered heterocyclic group having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the _cycloalkyl or heterocyclic group is optionally substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _1-4 alkyl and C _1-4 alkoxy; each of X ¹ , X ² , X ³ and X ⁴ is independently selected from CH and N; each of Y ¹ and Y ² is independently hydrogen, deuterium, or optionally substituted with 1 to 3 identical or different substituents independently selected from deuterium, halogen, cyano, C _2-3 alkynyl, C 1-4 alkoxy; the alkyl radical being selected from the group consisting of -C(O)NH-(C _1-4 H _3-9 ) and -C _{1-6 alkyl radical being substituted with the same or different substituents selected from -C(O)NH-(C 1-4 H 3-9 ); and Z is a C 1-8 alkyl radical} ; a C _1-6 alkoxy radical; a C _3-6 cycloalkyl radical; a C _6-12 aryl radical; a 3- to 12-membered heterocyclic radical having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 12-membered heteroaryl radical having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the alkyl radical, alkoxy radical, cycloalkyl radical, aryl radical, heterocyclic radical or heteroaryl radical is each optionally substituted with the same or different substituents selected independently from halogen, cyano, C _1-4 alkyl radical, C _1-4 alkoxy radical and C _3-6 cycloalkyl radical, wherein the C _1-4 alkyl radical is optionally substituted with 1 to 3 heteroatoms selected from C 6-12 or ^Y1 and Z together with the carbon to which they are attached form a _C3-6 cycloalkyl group; a _C6-12 aryl group; a 3-12 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or _{a 5-12} membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl group, aryl group, heterocyclic group or heteroaryl group is each optionally substituted with 1 to 3 same or different substituents independently selected from cyano, _C1-4 alkyl, _C1-4 alkoxy, _C6-10 aryl and halogen, wherein the C1-4 alkyl group is optionally substituted with 1 to 3 same or different substituents independently selected from C1-4 alkoxy and halogen, and wherein the _C1-4 alkyl group is optionally substituted with 1 to 3 same or different substituents independently selected from _C1-4 alkoxy and halogen, and wherein the C _{The 6-10} aryl group is optionally substituted with 1 to 3 identical or different substituents independently selected from C _1-4 alkyl, C _1-4 alkoxy and halogen, and Y ² is hydrogen or deuterium.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia): or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, R ² is hydrogen.

In some embodiments of the compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, R ⁴ is C _1-3 alkyl optionally substituted with 1 to 3 identical or different substituents independently selected from cyano and F. In some embodiments of the compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, R ⁴ is -CH ₃ .

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X ¹ is CH, X ² is CH, X ³ is CH, and X ⁴ is CH.

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X ¹ is C(R ³ ), X ² is CH, X ³ is CH, and X ⁴ is CH.

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, ^X1 is C( ^R3 ), ^X2 is CH, ^X3 is C( ^R3 ), and ^X4 is CH.

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X ¹ is N, X ² is CH, X ³ is CH, and X ⁴ is C(R ³ ).

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X ¹ is CH, X ² is N, X ³ is CH, and X ⁴ is C(R ³ ).

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X ¹ is C(R ³ ), X ² is N, X ³ is CH, and X ⁴ is CH.

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, ^X1 is C( ^R3 ), ^X2 is N, ^X3 is CH, and ^X4 is C( ^R3 ).

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, ^X1 is C( ^R3 ), ^X2 is CH, ^X3 is C( ^R3 ), and ^X4 is CH.

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X ¹ is N, X ² is CH, X ³ is N, and X ⁴ is C(R ³ ).

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X ¹ is C(R ³ ), X ² is N, X ³ is N, and X ⁴ is CH.

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X ¹ is CH, X ² is N, X ³ is N, and X ⁴ is CH.

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X ¹ is N, X ² is CH, X ³ is CH, and X ⁴ is CH.

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, ^X1 is N, ^X2 is CH, ^X3 is N, and ^X4 is CH.

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X ¹ is CH, X ² is N, X ³ is C(R ³ ), and X ⁴ is CH.

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, X ¹ is CH, X ² is N, X ³ is CH, and X ⁴ is CH.

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, Y ² is hydrogen.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIa): or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIb): or a pharmaceutically acceptable salt thereof, wherein each R ³ may be the same or different.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIc): . or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IId): . or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIe): . or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIf): or a pharmaceutically acceptable salt thereof, wherein each R ³ may be the same or different.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIg): or a pharmaceutically acceptable salt thereof, wherein each R ³ may be the same or different.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIh): . or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIi): . or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIj): . or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIk): . or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIl): . or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIm): . or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIn): . or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (IIo): . or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ¹ is hydrogen.

In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is ^C1-6 alkyl, _C2-6 alkenyl or _C2-6 alkynyl, each of which is optionally substituted with 1 to 4 ^R1A which may be the same or different, wherein each ^R1A is independently selected _from halogen; cyano; nitro; pendoxy; _C1-4 alkyl; C2-6 alkynyl; _3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 R ^1B2 and R ^1B3 are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein each R ^1A is alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted with 1 to 4 identical or different R ^1C , wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen or C _1-6 alkyl, and wherein each R ^1B1 , R ^1B2 and R ^1B3 alkyl and each R ^1B1 , R ^1B2 and R ^1B3 cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is ^C1-6 alkyl, _C2-6 alkenyl or _C2-6 alkynyl, each of which is optionally substituted with 1 to 4 identical or different ^R1A , wherein each ^R1A is independently selected _from halogen; cyano; pendoxy; _C1-4 alkyl; C2-6 alkynyl; _3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 , R ^1B2 and R ^1B3 are independently hydrogen or C _1-6 alkyl, wherein each R ^1A is alkyl, cycloalkyl, heterocyclo, aryl, and heteroaryl optionally substituted with 1 to 4 identical or different R ^1C , wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), and wherein each R ^1D1 and R ^1D2 are independently hydrogen or C _1-6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi) or their pharmaceutically acceptable salts, R ¹ is C _1-6 alkyl or C _2-6 alkynyl, each optionally substituted by 1 to 4 identical or different R ^1A , wherein each R ^1A is independently selected from halogen, cyano, hydroxyl, C _1-4 alkoxy and C _3-6 cycloalkyl. In some embodiments, each halogen in R ^1A or R ^1C is -F. In some embodiments, each R ^1A is independently selected from -F, -CN, -OH, -OCH ₃ or cyclopropyl. In some embodiments, each halogen in R ^1A or R ^1C is -F. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is ^C1-6 alkyl or _C2-6 alkynyl, each of which is independently substituted with 1 to 4 identical or different ^R1A , wherein each ^R1A is independently selected _from -F, -CN, -OH, _-OCH3 or cyclopropyl. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ¹ is -CH ₃ , -CHF ₂ , -CF ₃ , .

In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ¹ is -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein each C _1-6 alkyl or C _3-6 cycloalkyl is optionally substituted with 1 to 4 identical or different R ^1E , wherein each R ^1E is independently selected from halogen; cyano; hydroxy; pendant; C _1-4 alkyl; C _3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -OR ^1F1 ; -N(R ^1F1 )(R ^1F2 ); -C(O)N(R ^1F1 )(R 1F2 ⁾ ; -NR ^1F1 C(O)R ^1F2 ; -S(O) _0-2 R ^1F1 ; -S(O) ₂ N(R ^1F1 )(R ^1F2 ) and -NR ^1F1 S(O) ₂ R ^1F2 , wherein each R ^1F1 and R ^1F2 are independently hydrogen or C _1-6 alkyl, wherein each R ^1E alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted by 1 to 3 identical or different R ^1G , and each R ^1G is independently C _1-4 alkyl, C _1-4 alkoxy, hydroxyl, halogen or cyano. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ¹ is -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^{1D1 and R 1D2 are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein each C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with 1 to 3 identical or different -R 1E , wherein each R 1E is independently selected from halogen and -C(O)N(R 1F1 )(R 1F1 ), wherein each -R 1F1} _{and -R 1D2 are independently hydrogen, C 1-6 alkyl or C 3-6} ^cycloalkyl , wherein each C _1-6 alkyl or C _3-6 cycloalkyl is optionally substituted with 1 to 3 identical or different -R ^1E , wherein each R ^1E is independently selected from halogen and -C(O)N(R ^1F1 )(R ^1F1 ), wherein each -R ^1F1 and -R ^1F1 is independently hydrogen or C _1-4 alkyl. In some embodiments, each -R ^1E halogen is -F. In some embodiments, each -R ^1G halogen is -F. In some embodiments of the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or a pharmaceutically acceptable salt thereof, R ¹ is -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently -H, -CH ₃ , -C ₂ H ₅ or -C(CH ₃ ) ₃ . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ¹ is .

In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ^is a _C3-10 cycloalkyl group optionally substituted with 1 to 4 identical or different ^R1A groups, wherein each ^{R1A group} is independently selected from halogen; cyano; nitro; pendooxy; _C1-4 alkyl; _C3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered aryl group; a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N( ^R1B1) ; )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 , R ^1B2 and R ^1B3 are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein each R ^1A is alkyl, cycloalkyl, heterocyclic, aryl and optionally heteroaryl substituted with 1 to 4 identical or different R ^1C , and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 is independently hydrogen or C _1-6 alkyl, and wherein each R ^1B1 and R ^1B2 alkyl and each R ^1B1 and R ^1B2 cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ^is a _C3-10 cycloalkyl group optionally substituted with 1 to 4 identical or different ^R1A groups, wherein each ^{R1A group} is independently selected from halogen; cyano; pendooxy; _C1-4 alkyl; _C3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered aryl group; a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N( ^R1B1 )(R1 -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O ⁾ N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 , R ^1B2 and R ^1B3 are independently hydrogen or C _1-6 alkyl, wherein each R ^1A is alkyl, cycloalkyl, heterocyclic, aryl and optionally heteroaryl substituted with 1 to 4 identical or different R ^1C , and wherein each R ^1C is independently C ^{R 1D1} _and R ^{1D2 are} independently _{hydrogen or C 1-6} ^{alkyl .} In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ^is a _C3-10 cycloalkyl group optionally substituted with 1 to 4 identical or different ^R1A , wherein each ^R1A is independently selected from halogen; cyano; nitro; pendooxy; _C1-4 alkyl; a 3-6 membered heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5 or 6 membered heteroaryl group having 1 or 2 heteroatoms independently selected from nitrogen or oxygen; ^-OR1B1 ; and -C(O)N( ^R1B1 )( ^R1B2 ), wherein each R ^1B1 and R ^1B2 are independently hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl, and wherein each R ^1A C _1-4 alkyl is optionally substituted with 1 to 3 halogens, and each heteroaryl in R ^1A is optionally substituted with 1 to 3 C _1-4 alkyls, and wherein each R ^1B1 and R ^1B2 alkyl and each R ^1B1 and R ^1B2 cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ¹ is a C _3-10 cycloalkyl group optionally substituted with 1 to 4 identical or different R ^1A , wherein each R ^1A is independently selected from halogen; cyano; pendooxy; C _{1-4 alkyl; a 3-6 membered heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5 or 6 membered heteroaryl group having 1 or 2 heteroatoms independently selected from nitrogen or oxygen; -OR 1B1 ; and -C(O)N(R 1B1 )(R 1B2 ), wherein each R 1 is C 3-10} cycloalkyl group optionally substituted with 1 to 4 identical or different R 1A, wherein each R 1A is independently selected from halogen; cyano; pendooxy; C ^1-4 alkyl; a 3-6 membered heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5 or 6 membered heteroaryl group having 1 or 2 heteroatoms independently selected from nitrogen or ^{oxygen ;} R ^1B1 and R ^1B2 are independently hydrogen or C _1-4 alkyl, and each R ^1A C _1-4 alkyl is optionally substituted with 1 to 3 halogens, and each heteroaryl in R ^1A is optionally substituted with 1 to 3 C _1-4 alkyls. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ¹ is cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 4 identical or different R ^1A each independently selected from the following: -F, -Cl, -CN, =O, -OH, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ -OH, -CH ₂ -NH ₂ , -OCH ₃ , -NH ₂ , -NH-CH ₂ -CF ₃ , , -NO ₂ , cyclopropyl, isoxazolyl, phenyl, pyridinyl and -C(O)NH ₂ , wherein each isoxazolyl or pyridinyl is optionally substituted with 1 to 2 -F or -CH ₃ groups. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ¹ is cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 4 identical or different R ^1A each independently selected from the following: -F, -Cl, -CN, =O, -OH, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ -OH, -CH ₂ -NH ₂ , -OCH ₃ , -NH ₂ , cyclopropyl, isoxazolyl, phenyl, pyridinyl and -C(O)NH ₂ , wherein each isoxazolyl or pyridinyl is optionally substituted with 1 to 2 -F or -CH _3. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), or pharmaceutically acceptable salts thereof, R ¹ is cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 4 identical or different R ^1A each independently selected from the following: -F, -Cl, -CN, =O, -OH, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -OCH ₃ , isoxazolyl, pyridinyl and -C(O)NH ₂ , wherein each isoxazolyl or pyridinyl is optionally substituted with 1 to 2 -CH ₃ . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ¹ is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R ¹ is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R ¹ is In some embodiments, the C _3-10 cycloalkyl group is a C _5-10 bicyclic cycloalkyl group. In some embodiments, the C _5-10 bicyclic cycloalkyl group is a C _5-8 bridged bicyclic cycloalkyl group. In some embodiments, the C _5-8 bridged bicyclic cycloalkyl group is a bicyclopentyl group or a bicyclooctyl group, each of which is optionally substituted with 1 to 3 identical or different substituents independently selected from the following: -F, -Cl, -OH, -CN, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -O-CH ₃ , -NH-CO-CH ₃ , -SO ₂ -CH ₃ and oxocarbonyl. In some embodiments, the C _5-8 bridged bicyclic cycloalkyl is dicyclopentyl or dicyclooctyl, each of which is optionally substituted with 1 to 3 identical or different substituents independently selected from the following: -F, -Cl, -OH, -CN, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -O-CH ₃ and oxocarbonyl. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R ¹ is In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), (IIo) or their pharmaceutically acceptable salts, R ¹ is In some embodiments, the C _5-10 bicyclic cycloalkyl is a C _5-10 spirobicyclic cycloalkyl. In some embodiments, the C _5-10 spirobicyclic cycloalkyl is a spiropentyl, spirohexenyl, spiroheptyl or spirodecanyl, each of which is optionally substituted with 1 to 4 identical or different R ^1A , wherein each R ^1A is independently selected from -F, -Cl, -OH, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CN and -O-CH ₃ . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ¹ is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R ¹ is .

In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, ^R is a 3- to 10-membered heterocyclic group having 1 to 4 ^heteroatoms independently selected from nitrogen, oxygen and sulfur, and the 3- to 10-membered heterocyclic group is optionally substituted with 1 to 4 identical or different R, wherein each R ^is independently selected from halogen; cyano; nitro; pendoxy; _C1-4 alkyl; C _3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 R ^1B2 and R ^1B3 are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein each R ^1A is alkyl, cycloalkyl, heterocyclic, aryl and is optionally substituted with 1 to 4 identical or different R ^1C , and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen or C _1-6 alkyl, and wherein each R ^1B1 and R ^1B2 alkyl and each R ^1B1 and R ^1B2 cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, ^R is a 3- to 10-membered heterocyclic group having 1 to 4 ^heteroatoms independently selected from nitrogen, oxygen and sulfur, and the 3- to 10-membered heterocyclic group is optionally substituted with 1 to 4 identical or different R, wherein each R ^is independently selected from halogen; cyano; pendolo; _C1-4 alkyl; C _3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 , R ^1B2 and R ^1B3 are independently hydrogen or C _1-6 alkyl, wherein each R ^1A is alkyl, cycloalkyl, heterocyclo, aryl, and heteroaryl optionally substituted with 1 to 4 identical or different R ^1C , and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen or C _1-6 alkyl. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, ^R is a 3-8 membered heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the 3-8 membered heterocyclic group is optionally substituted with 1 to 4 identical or different R ^1A each independently selected from halogen, cyano, oxo or C _1-4 alkyl, wherein each R ^1A C _1-4 alkyl is optionally substituted with 1 to 3 identical or different R ^1C , and wherein each R ^1C is independently C _1-4 alkoxy, halogen or cyano. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is azetidinyl, oxazolinyl, thiocyclobutyl, pyrrolidinyl, dioxolanyl, tetrahydropyranyl, piperidinyl or oxolinyl, each of which is optionally substituted with ¹ to 4 identical or different R selected independently from the following: -F, -Cl, -OH, -CN, ^-CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -C ₂ H ₅ , -CH ₂ -CF ₃ and -O-CH ₃ . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ^is azetyl, oxazoline, thiocyclobutyl, pyrrolidinyl, dioxolanyl, tetrahydropyranyl or oxolinyl, each of which is optionally substituted with 1 to 4 identical or different ^R1A each independently selected from the group consisting of -F, -Cl, -OH, -CN, _-CH3 , _-CH2F , _-CHF2 , _-CF3 and -O- _CH3 . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R ¹ is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R ¹ is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R ¹ 3 to 10 membered heterocyclic group forms a bicyclic heterocyclic group. In some embodiments, the bicyclic heterocyclic group is a bridged bicyclic heterocyclic group. In some embodiments, the bridged bicyclic heterocyclic group is an oxahertzbicyclohexyl group optionally substituted with 1 to 4 identical or different R ^1A , wherein each R ^1A is independently selected from -F, -Cl, -OH, -CN, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ and -O-CH ₃ . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or a pharmaceutically acceptable salt thereof, R ¹ is In some embodiments, the bicyclic heterocyclic group is a fused bicyclic heterocyclic group. In some embodiments, the fused bicyclic heterocyclic group is an oxahedral hexadecyl group optionally substituted with 1 to 4 identical or different R ^1A , wherein each R ^1A is independently selected from -F, -Cl, -OH, -CN, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ and -O-CH ₃ . In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R ¹ is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R ¹ is . In some embodiments, the bicyclic heterocyclic group is a spirobicyclic heterocyclic group. In some embodiments, the spirobicyclic heterocyclic group is an oxahedral spiroheptane optionally substituted with 1 to 4 identical or different substituents, each of which is independently selected from -F, -Cl, -OH, -CN, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ and -O-CH ₃ . In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, R ¹ is .

In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is a 6- to 10-membered ^aryl group optionally substituted with ¹ to 4 identical or different R, wherein each R ^is independently selected from halogen; cyano; nitro; pendooxy; _C1-4 alkyl; _C3-10 cycloalkyl; a 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6- to 10-membered aryl group; a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N( ^R1B1 )(R1 -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O ⁾ N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 , R ^1B2 and R ^1B3 are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein each R ^1A is alkyl, cycloalkyl, heterocyclic, aryl and optionally heteroaryl substituted with 1 to 4 identical or different R ^1C , and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 is independently hydrogen or C _1-6 alkyl, and wherein each R ^1B1 and R ^1B2 alkyl and each R ^1B1 and R ^1B2 cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, R is a 6- to 10-membered ^aryl group optionally substituted with ¹ to 4 identical or different R, wherein each R ^is independently selected from halogen; cyano; pendoxy; _C1-4 alkyl; _C3-10 cycloalkyl; a 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6- to 10-membered aryl group; a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N( ^R1B1 )( ^R1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 , R ^1B2 and R ^1B3 are independently hydrogen or C _1-6 alkyl, wherein each R ^1A is alkyl, cycloalkyl, heterocyclic, aryl and optionally heteroaryl substituted with 1 to 4 identical or different R ^1C , and wherein each R ^1C is independently C In some embodiments, ^{R 1 is phenyl optionally substituted with 1 to 4 identical or different R 1A, wherein each R 1A is independently selected from halogen, cyano, C 1-3 alkyl or C 1-4 alkoxy. In some embodiments, R 1} _is ^{phenyl optionally substituted with} ₁ ^to 3 identical or different R ^1A , wherein each R ^{1A is} independently selected ^from -F, Cl _, CN or -CH _{3 .}

In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, ^R is a 5-10 membered heteroaryl group having 1 to 4 ^heteroatoms independently selected from nitrogen, oxygen and sulfur, the 5-10 membered heteroaryl group is optionally substituted with 1 to 4 identical or different R, wherein each R ^is independently selected from halogen; cyano; nitro; pendant; C _1-4 alkyl; C _3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 R ^1B2 and R ^1B3 are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein each R ^1A is alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted with 1 to 4 identical or different R ^1C , and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen or C _1-6 alkyl, and wherein each R ^1B1 and R ^1B2 alkyl and each R ^1B1 and R ^1B2 cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, ^R is a 5-10 membered heteroaryl group having 1 to 4 ^heteroatoms independently selected from nitrogen, oxygen and sulfur, the 5-10 membered heteroaryl group is optionally substituted with 1 to 4 identical or different R, wherein each R ^is independently selected from halogen; cyano; pendoxy; _C1-4 alkyl; C _3-10 membered cycloalkyl; 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 6-10 membered aryl group; 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ); -S(O) _0-2 R ^1B1 ; -S(O) ₂ N(R ^1B1 )(R ^1B2 ) and -NR ^1B1 S(O) ₂ R ^1B2 , wherein each R ^1B1 , R ^1B2 and R ^1B3 are independently hydrogen or C _1-6 alkyl, wherein each R ^1A is alkyl, cycloalkyl, heterocyclo, aryl, and heteroaryl optionally substituted with 1 to 4 identical or different R ^1C , and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen or C _1-6 alkyl. In some embodiments, R ¹ is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridonyl, pyrimidinyl, pyrimidinyl, benzisoxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each of which is optionally substituted with 1 to 4 identical or different R ^1A , wherein each R ^1A is independently selected from halogen; cyano; oxo; C _1-4 alkyl; C 3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen and oxygen; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 and -S(O) _0-2 R ^1B1 , wherein each R ^1B1 and R ^1B2 are independently hydrogen or C _3-10 cycloalkyl; _wherein each R ^1A alkyl, cycloalkyl and heterocyclic group is optionally substituted by 1 to 4 identical or different R ^{1C groups} , and wherein each R ^1C is independently C _1-4 alkyl, halogen or cyano. In some embodiments, R ¹ is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridonyl, pyrimidinyl, pyrimidinyl, benzoisoxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each of which is optionally substituted with 1 to 4 identical or different R ^1A , wherein each R ^1A is independently selected from halogen, cyano, oxo, methyl, cyclopropyl, oxolinyl, -N(R ^1B1 )(R ^1B2 ), -OR ^1B1 and -S(O) _0-2R ^1B1 , wherein each R ^1B1 and R ^1B2 are independently hydrogen or methyl, wherein each R ^1A methyl, cyclopropyl and oxolinyl are optionally substituted with 1 to 4 identical or different R 1A In some embodiments, R ¹ is substituted with ^{1 to 4} identical or different substituents independently selected from the following: halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy. In some embodiments, R ¹ is substituted with 1 to 4 identical or different substituents independently selected from the following: halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy. In some embodiments, R ¹ is substituted with 1 to 4 identical or different substituents independently selected from the following: halogen, _{cyano, C 1-4 alkyl} or _{C 1-4} alkoxy. In some embodiments, R ¹ is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridonyl, pyrimidinyl, pyrimidinyl, benzisoxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each of which is optionally substituted with 1 to 3 independently selected from -F, -Cl, -CN, -CH ₃ , -CHF ₂ , -CF ₃ , -OCH ₃ , -NH ₂ , -N(CH ₃ ) ₂ , -SO _{2 ,} -CH ₃ , ... In some embodiments, R ¹ is imidazolyl, pyrazolyl or pyridyl, each of which is optionally substituted with 1 to 3 identical or different substituents independently selected from the following: -F, -Cl, -CN or -CH ₃ . In some embodiments, R ¹ is In some embodiments, R ¹ is In some embodiments of the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi) or (IIn), or a pharmaceutically acceptable salt thereof, each R ³ is independently selected from deuterium, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, -OR ^2A1 and -N(R ^2A1 )(R ^2A2 ), wherein the C _1-6 alkyl is optionally substituted with 1 to 3 identical or different substituents independently selected from C _1-4 alkoxy and halogen, and wherein each R ^2A1 and R ^2A2 is independently hydrogen or C _1-4 alkyl substituted with 1 to 3 identical or different halogens. In some embodiments, each R ³ is independently selected from C _1-6 alkyl, optionally substituted with 1 to 3 identical or different substituents, said substituent(s) being independently selected from halogen, cyano, C _1-4 alkoxy and C _3-10 cycloalkyl. In some embodiments of the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi) or (IIn) or a pharmaceutically acceptable salt thereof, R ³ is -CH _3. In some embodiments of the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi) or (IIn) or a pharmaceutically acceptable salt thereof, R ³ is halogen. In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIn), or a pharmaceutically acceptable salt thereof, R is ^-F . In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIn), or a pharmaceutically acceptable salt thereof, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

In some embodiments of the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, each of ^Y1 and ^Y2 _is independently hydrogen, deuterium or C1-6 alkyl substituted with 1 to ₃ identical or different substituents independently selected from halogen, cyano, _C2-3 alkynyl, _C1-4 alkoxy and -C(O)NH-( _C1-4H3-9 ). In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, ^Y is hydrogen, deuterium or C _1-6 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano, C _2-3 alkynyl, C _1-4 alkoxy and -C(O)NH-(C _1-4 H _3-9 ). In some embodiments, _{Y is} C _1-4 alkyl substituted with 1 to 3 identical or different substituents independently selected from halogen, cyano and C _1-4 alkoxy, and Y is hydrogen. In some embodiments, Y ₁ is methyl optionally substituted with 1 to 3 identical or different substituents each independently selected from -F, -Cl, -CN, and -O-CH _3. In some embodiments, Y ₁ is -CH ₃ or -CH ₂ F.

In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or their pharmaceutically acceptable salts, Z is _C6-12 aryl optionally substituted with 1 to 3 identical or different substituents each independently selected from halogen, cyano, _C1-4 alkyl, _C1-4 alkoxy and _C3-6 cycloalkyl, wherein the _C1-4 alkyl is optionally substituted with 1 to 3 identical or different substituents each independently selected from _C1-4 alkoxy and halogen. In some embodiments, Z is phenyl optionally substituted with 1 to 3 identical or different substituents each independently selected from halogen and _C1-4 alkyl. In some embodiments, Z is phenyl optionally substituted with 1 to 3 identical or different substituents each independently selected from -F and -Cl. In some embodiments, Z is In some embodiments, Z is a 5- or 6-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl group is optionally substituted with 1 to 3 identical or different substituents independently selected from halogen and C _1-4 alkyl. In some embodiments, Z is a pyridyl group optionally substituted with 1 to 3 identical or different substituents independently selected from -F, -Cl, -Br and -CH _3. In some embodiments, Z is .

In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo), or pharmaceutically acceptable salts thereof, Y ₁ is -CH ₃ and Z is In some embodiments of the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or pharmaceutically acceptable salts thereof, Y ₁ is -CH ₃ and Z is .

In some embodiments, the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: , or their pharmaceutically acceptable salts.

In some embodiments, the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), (IIo) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: , or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or their pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I), (Ia) or (IIo) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I), (Ia) or (IIe) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I), (Ia) or (IIe) or a pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salts.

In some embodiments, the compound of formula (I), (Ia) or (IIe) or a pharmaceutically acceptable salt thereof is: , or a pharmaceutically acceptable salt thereof. Pharmaceutical composition and administration mode

In addition, the present invention provides a pharmaceutical composition comprising at least one compound of the present invention, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvent thereof, together with a pharmaceutically acceptable carrier as an active ingredient.

The pharmaceutical compositions of the present invention may further comprise one or more other compounds as active ingredients, such as prodrug compounds or other enzyme inhibitors.

The composition is suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (transoral), pulmonary (nasal or intrabuccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition to be treated and the nature of the active ingredient. It may be conveniently presented in unit dosage form and prepared by any method well known in the art of pharmacy.

In practical use, the compounds of the present invention can be combined as active ingredients in intimate admixtures with pharmaceutical carriers according to conventional pharmaceutical mixing techniques. The carrier can take a variety of forms depending on the form of preparation required for administration (e.g., oral or parenteral (including intravenous)). In preparing compositions for oral dosage forms, in the case of oral liquid preparations such as suspensions, elixirs and solutions; or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like, in the case of oral solid preparations such as powders, hard and soft capsules and tablets (where solid oral preparations are preferred over liquid preparations), any of the usual pharmaceutical media such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be employed.

Tablets and capsules represent the most advantageous oral unit dosage forms because they are easy to administer, in which case solid pharmaceutical carriers are used. Tablets may be coated by standard aqueous or non-aqueous techniques, if necessary. Such compositions and formulations should contain at least 0.1% of the active compound. The percentage of the active compound in such compositions may of course vary and may preferably be between about 2% and about 60% of the unit weight. The amount of the active compound in such therapeutically applicable compositions is such that an effective dose will be obtained. The active compound may also be administered intranasally, for example, in the form of drops or sprays.

Tablets, pills, capsules and the like may also contain binders such as gum tragacanth, gum arabic, corn starch or gelatin; formulators such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose or saccharin. When the unit dosage form is a capsule, in addition to the above types of materials, the unit dosage form may contain a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with insect glue, sugar, or both. In addition to the active ingredient, a syrup or elixir may contain sucrose as a sweetener, methyl and propyl parabens as preservatives, dyes, and flavorings such as cherry or orange flavor.

In some embodiments, the compounds of the present invention may also be used as salts with various anti-cations to obtain orally effective formulations.

The compounds of the present invention may also be administered parenterally. Solutions or suspensions of the active compounds may be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it is easy to inject. It must be stable under the conditions of manufacture and storage and must be preserved to prevent the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils.

Any suitable route of administration for providing an effective dose of the compounds of the present invention to mammals, especially humans, may be used. For example, oral, rectal, topical, parenteral, ophthalmic, pulmonary, nasal and the like may be used. Dosage forms include tablets, dragees, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. In some embodiments, the compounds of the present invention are administered orally. Kits

Also provided herein are kits comprising a compound of the invention or a pharmaceutically acceptable salt, tautomer, stereoisomer, stereoisomer mixture, prodrug or deuterated analog thereof, and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the invention or a pharmaceutically acceptable salt, tautomer, stereoisomer, stereoisomer mixture, prodrug or deuterated analog thereof, and a label and/or instructions for using the compound to treat an indication, including a disease or condition described herein.

Also provided herein are articles of manufacture that include a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, stereoisomer mixture, prodrug, or deuterated analog thereof in a suitable container. The container may be a vial, jar, ampoule, pre-filled syringe, and intravenous bag. Treatment methods and uses

The present invention further relates to the use of the compounds disclosed herein for treating and/or preventing diseases and/or conditions by binding to LPAR1 by the compounds. In addition, the present invention relates to the use of the compounds for preparing a medicament for treating and/or preventing diseases and/or conditions by binding to LPAR1 by the compounds.

The pharmaceutical compositions mentioned herein can be prepared by known processes, comprising combining a compound according to the present invention with a pharmaceutically acceptable carrier.

In some embodiments, provided herein is a method for treating and/or preventing an LPAR1-mediated disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof.

In some embodiments, LPAR1-mediated diseases or conditions include those diseases or conditions in which an absolute or relative excess of LPA is present and/or observed.

In some embodiments, the LPAR1-mediated disease or condition comprises fibrosis, wound healing, cancer, pain, respiratory disorders, allergic disorders, nervous system disorders, cardiovascular disorders, or inflammatory disorders.

In some embodiments, the disease or condition of LPAR1 mediation is interstitial lung disease (ILD). In some embodiments, interstitial lung disease (ILD) is non-specific interstitial pneumonia (NSIP), sarcoidosis, asbestosis, ILD associated with occupational exposure, progressive fibrosing ILD, idiopathic interstitial pneumonia (IIP), interstitial lung disease associated with connective tissue disease (CTD-ILD), ILD associated with rheumatoid arthritis, ILD associated with scleroderma, or extrinsic alveolitis.

In some embodiments, the LPAR1-mediated disease or condition is chronic kidney disease (CKD). In some embodiments, the chronic kidney disease is glomerulopathy, membranous glomerulopathy, polycystic nephropathy, IgA nephropathy, focal segmental glomerulosclerosis (FSGS) or Alport Syndrome.

In some embodiments, the LPAR1-mediated disease or condition comprises fibrosis. In some embodiments, fibrosis comprises pulmonary fibrosis, renal fibrosis, hepatic fibrosis, ocular fibrosis or cardiac fibrosis.

In some embodiments, the LPAR1-mediated disease or condition comprises pulmonary fibrosis. In some embodiments, pulmonary fibrosis comprises idiopathic pulmonary fibrosis (IPF). In some embodiments, pulmonary fibrosis comprises progressive fibrotic interstitial lung disease (PF-ILD). In some embodiments, pulmonary fibrosis includes pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury, and acute respiratory distress (including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-septicemia-induced, and inhalation-induced).

In some embodiments, LPAR1-mediated diseases or conditions include renal fibrosis. In some embodiments, renal fibrosis includes chronic renal pathologies associated with: injury/fibrosis (renal fibrosis), for example, glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allogeneic transplantation, and Allport; intestinal fibrosis, for example, scleroderma and radiation-induced intestinal fibrosis.

In some embodiments, LPAR1-mediated diseases or conditions include liver fibrosis. In some embodiments, liver fibrosis includes cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection or virus-induced liver fibrosis (e.g., chronic HCV infection) and autoimmune hepatitis.

In some embodiments, the LPAR1-mediated disease or condition comprises head and neck fibrosis, such as radiation-induced.

In some embodiments, the LPAR1-mediated disease or condition comprises corneal scarring, for example, due to laser-assisted in situ keratomileusis (LASIK), corneal transplantation or trabeculectomy. In some embodiments, the compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn) or (IIo) or a pharmaceutically acceptable salt thereof is used to improve decreased corneal sensitivity caused by corneal surgery, such as LASIK or cataract surgery, decreased corneal sensitivity caused by corneal degeneration, and dry eye symptoms caused thereby. In some embodiments, the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo) or their pharmaceutically acceptable salts are used to treat or prevent ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis. In some embodiments, the compounds of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (III), (IIm), (IIn), or (IIo) or their pharmaceutically acceptable salts are used to treat or prevent Sjogren's disease or inflammatory diseases with dry eye symptoms.

In some embodiments, the LPAR1-mediated disease or condition comprises another fibrotic condition, such as hypertrophic scars and keloids (e.g., burn-induced or surgical), sarcoidosis, scleroderma, spinal cord injury/fibrosis, bone marrow fibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and Peyronie's disease.

In some embodiments, the LPAR1-mediated disease or condition comprises pain. In some embodiments, the pain comprises neuropathic pain. In some embodiments, the pain comprises acute pain. In some embodiments, the pain comprises chronic pain.

In some embodiments, the LPAR1-mediated disease or condition comprises cancer. In some embodiments, cancer comprises ovarian cancer, colon cancer, prostate cancer, breast cancer, melanoma, head and neck cancer, intestinal cancer (colorectal cancer) and thyroid cancer. In some embodiments, cancer comprises solid tumors, such as (such as bladder, intestine, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma) or blood tumors (such as leukemia) with or without metastasis at any stage of the disease. In some embodiments, cancer comprises solid tumors, such as (such as bladder, intestine, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma) or blood tumors (such as leukemia) with or without metastasis at any stage of the disease. In the embodiments, the cancer includes acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, coccygeal cancer, astrocytoma, atypical teratoid/bar tumor, basal cell carcinoma, bile duct carcinoma, bladder cancer, bone cancer (osteosarcoma and malignant fibromyoma), brain stem neurofibroma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt's lymphoma lymphoma), cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, colorectal cancer, cranio-pharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing's sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, neuroglioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma lymphoma), hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia macroglobulinemia), medulloblastoma, medullary epithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibroblastic tumor of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low-grade malignant latent tumor, pancreatic cancer, papilloma, epithelial cell carcinoma, Thyroid cancer, penile cancer, pharyngeal cancer, intermediately differentiated pineal parenchymal tumor, pinealoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell adenocarcinoma/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's sarcoma family of tumors, sarcoma, Kaposi's sarcoma, Sezary syndrome syndrome), skin cancer, small cell lung cancer, small intestinal cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms tumor.

In some embodiments, LPAR1-mediated diseases or conditions include respiratory or allergic diseases. In some embodiments, respiratory or allergic diseases include asthma, peribronchial fibrosis, obstructive bronchitis, and chronic obstructive pulmonary disease (COPD). In some embodiments, COPD includes chronic bronchitis or emphysema, pulmonary hypertension, pulmonary interstitial fibrosis and/or airway inflammation and cystic fibrosis. In some embodiments, respiratory diseases include adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, and hypoxia.

In some embodiments, LPAR1-mediated diseases or conditions include nervous system disorders. In some embodiments, nervous system disorders include Alzheimer's Disease, brain edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson's Disease, neurological conditions found after blunt or surgical trauma (including postoperative cognitive dysfunction and spinal cord or brain stem damage), and neurological aspects of diseases such as degenerative disc disease and sciatica.

In some embodiments, the LPAR1-mediated disease or condition comprises a cardiovascular disorder. In some embodiments, the cardiovascular disorder includes arrhythmias (atrial or ventricular or both); atherosclerosis and its sequelae; angina; heart rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis; stroke; peripheral obstructive arterial disease of a limb, organ or tissue; reperfusion injury following ischemia of the brain, heart or other organs or tissues; endotoxin, surgical or traumatic shock; hypertension; valvular heart disease; heart failure; abnormal blood pressure; shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities and cardiovascular insufficiency limited to a single organ or tissue.

In some embodiments, LPAR1-mediated diseases or conditions include pulmonary fibrosis, renal fibrosis, hepatic fibrosis, scarring, asthma, rhinitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, pulmonary interstitial fibrosis, arthritis, allergies, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative disorders, and inflammatory conditions.

In some embodiments, the LPAR1-mediated disease or condition is a liver disease. In some embodiments, the liver disease is hepatitis C, liver cancer, familial mixed hyperlipidemia, non-alcoholic fatty liver disease (NAFLD), progressive familial intrahepatic cholestasis, primary biliary cirrhosis (PBC) or (PSC). In some embodiments, the liver disease is PSC. In some embodiments, the liver disease comprises portal hypertension. In some embodiments, liver cancer comprises hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma or hemangiosarcoma. In some embodiments, liver cancer comprises HCC. In some embodiments, NAFLD comprises fatty degeneration. In some embodiments, NAFLD comprises NASH. In some embodiments, NAFLD or NASH comprises liver fibrosis. In some embodiments, NAFLD or NASH comprises cirrhosis. In some embodiments, NAFLD or NASH comprises compensatory cirrhosis. In some embodiments, NAFLD or NASH comprises decompensated liver fibrosis. In some embodiments, NAFLD comprises HCC. In some embodiments, the liver disease is NASH.

In some embodiments, provided herein is a method for treating and/or preventing NAFLD or NASH in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof. In some embodiments, NAFLD or NASH comprises liver fibrosis. In some embodiments, NAFLD or NASH comprises cirrhosis. In some embodiments, cirrhosis is compensatory cirrhosis. In some embodiments, cirrhosis is decompensated cirrhosis. In some embodiments, NAFLD or NASH comprises HCC.

In some embodiments, provided herein is a method of preventing a liver disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) or a pharmaceutically acceptable salt thereof. In some embodiments, the liver disease or condition is liver fibrosis. In some embodiments, the liver disease or condition is cirrhosis. In some embodiments, the cirrhosis is compensatory cirrhosis. In some embodiments, the cirrhosis is decompensated cirrhosis. In some embodiments, the liver disease or condition is HCC.

In some embodiments, the present invention relates to the use of a compound according to formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention and/or treatment of an LPAR1-mediated disease or condition disclosed herein. Dosage

The effective dosage of the active ingredient employed may vary depending on the specific compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosages can be readily determined by one skilled in the art.

When treating or preventing LPAR1-mediated diseases or conditions targeted by the compounds of the present invention, generally satisfactory results are obtained when the compounds of the present invention are administered in a daily dose of about 0.1 mg to about 300 mg/kg of animal body weight. In some embodiments, the compounds of the present invention are administered in a single daily dose or in divided doses two to six times a day or in a sustained release form. For most large mammals, the total daily dose is about 1 mg to about 1000 mg, or about 1 mg to about 50 mg. For a 70 kg adult, the total daily dose will generally be about 0.1 mg to about 200 mg. This dosing regimen can be adjusted to provide the best therapeutic response. In some embodiments, the total daily dose is about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 20 mg, or about 1 mg to about 10 mg.

The compounds or compositions of the present application may be administered once, twice, three times or four times a day using any suitable mode described above. In addition, administration or treatment with the compound may continue for multiple days; for example, for a treatment cycle, treatment will generally continue for at least 7 days, 14 days or 28 days. Treatment cycles are often alternating with rest periods of about 1 to 28 days, usually about 7 days or about 14 days between each cycle. In other embodiments, treatment cycles may also be continuous.

In some embodiments, the methods provided herein comprise administering to a subject an initial daily dose of about 1 to 800 mg of a compound described herein, and increasing the dose in increments until clinical efficacy is achieved. The dose may be increased in increments of about 5, 10, 25, 50, or 100 mg. The dose may be increased daily, every other day, twice a week, or once a week. Combinations

In some embodiments, a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

In some embodiments, the pharmaceutical compositions provided herein have a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), or (IIo) provided herein, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

In some embodiments, one or more additional therapeutic agents are selected from angiotensin converting enzyme (ACE) inhibitors, adenosine A3 receptor agonists, adiponectin receptor agonists, AKT protein kinase inhibitors, AMP kinase activators, AMP activated protein kinase (AMPK) activators, starch receptor agonists, angiotensin II AT-1 receptor antagonists, androgen receptor agonists, apoptosis signal regulating kinase 1 (ASK1) inhibitors, ATP citrate lyase inhibitors, apolipoprotein C3 (APOC3) antagonists, autophagy protein regulators, autocrine motor factor inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, bioactive lipids, Calcium-lowering hormone agonists, cannabinoid receptor modulators, apoptosis inhibitors, apoptosis stimulators-3, cathepsin inhibitors (e.g., cathepsin B inhibitors), caveolin-1 inhibitors, CCR2 chemokine antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, chloride channel stimulators, cholesterol solubilizers, CNR1 inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, cytochrome P450 2E1 (CYP2E1) inhibitors, diacylglycerol O-acyltransferase 1 inhibitors (DGAT1) inhibitors, diacylglycerol O-acyltransferase 1 inhibitors (DGAT2) inhibitors, CXCR4 chemokine antagonists, dipeptidyl peptidase, IV inhibitors, endosialin regulators, endothelial nitric oxide synthase stimulators, eosin ligand inhibitors, extracellular matrix protein regulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast activation protein (FAP) inhibitors, Fibroblast growth factor receptor ligands (e.g., FGF-15, FGF-19, FGF-21), fish oil, galectin-3 inhibitors, glucagon receptor agonists, glucagon-like peptide 1 receptor agonists, glucocorticoid receptor antagonists, glucose 6-phosphate 1-dehydrogenase inhibitors, glutaminase inhibitors, glutathione precursors, G protein-coupled cholic acid receptor 1 agonists, G protein-coupled receptor 84 antagonists, hedgehog (Hh) modulators, hepatitis C virus NS3 protease inhibitors, hepatocyte nuclear factor 4 α regulator (HNF4A), hepatocyte growth factor regulator, histone deacetylase inhibitor, HMG CoA reductase inhibitor, 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitor, hypoxia-inducing factor-2 α inhibitor, IL-1β antagonist, IL-6 receptor agonist, IL-10 agonist, IL-11 antagonist, IL-17 antagonist, ileal sodium bile acid symporter inhibitor, Insulin sensitizers, insulin ligand agonists, insulin receptor agonists, integrin modulators, integrin antagonists, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, Jak2 tyrosine kinase inhibitors, ketokinase (KHK) inhibitors, clonidine beta stimulators, leptin, leptin analogs, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptors, LPL gene stimulators, lysophosphatidic acid-1 receptor (LPAR-1) antagonists, aminoacyl oxidase homolog 2 (LOXL2) inhibitor, LXR inverse agonist, macrophage mannose receptor 1 regulator, matrix metalloproteinase (MMP) inhibitor, MCH receptor-1 antagonist, MEKK-5 protein kinase inhibitor, membrane copper amine oxidase (VAP-1) inhibitor, methionine aminopeptidase-2 inhibitor, methyl CpG binding protein 2 regulator, microRNA-132 (miR-132) antagonist, microRNA-21 (miR-21) inhibitor, mitochondrial uncoupling agent, mixed spectrum kinase-3 inhibitor, myelin alkaline protein stimulator, NACHT PYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase longevity protein-1 stimulators, NADPH oxidase inhibitors (NOX), niacin receptor 1 agonists, P2X7 purine receptor modulators, P2Y13 purine receptor stimulators, PDE 3 inhibitors, PDE 4 inhibitors, PDE 5 inhibitors, PDGF receptor β modulators, peptidyl-prolinyl cis-trans isomerase A inhibitors, phenylalanine hydroxylase stimulators, phospholipase C inhibitors, PPAR α agonists, PPAR γ agonists, PPAR δ agonists, PPAR γ modulators, PPAR α/δ agonists, PPAR α/γ/δ agonists, protease-activated receptor-2 antagonists, protein kinase regulators, rho-related protein kinase 2 (ROCK2) inhibitors, nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter-2 (SGLT2) inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, STAT-3 regulators, stearyl CoA desaturase-1 inhibitors, nitrosoglutathione reductase (GSNOR) enzyme inhibitors, interleukin signaling inhibitor-1 stimulators, interleukin signaling inhibitor-3 stimulators, spleen tyrosine kinase (SYK) inhibitors, transformation growth factor β (TGF-β), TGF-β antagonists (e.g., TGF-β1 antagonists, TGF-β2 antagonists, TGF-β3 antagonists, latent TGF β complex modulators), TGF-β receptor antagonists, transforming growth factor β-activated kinase 1 (TAK1), thyroid hormone receptor β agonists, Toll-like receptor (TLR)-4 antagonists, glutamine transaminase inhibitors, tumor necrosis factor α (TNFα) ligand inhibitors, tumor progression locus 2 (Tpl2) kinase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, WNT modulators, YAP/TAZ modulators and zonulin inhibitors.

Non-limiting examples of the one or more additional therapeutic agents include ACE inhibitors, such as enalapril; acetyl CoA carboxylase (ACC) inhibitors, such as NDI-010976 (firsocostat), DRM-01, gemcabene, PF-05175157, QLT-091382, or PF-05221304; acetyl CoA carboxylase/diacylglycerol O-acyltransferase 2 inhibitors, such as PF-07055341; acetaldehyde dehydrogenase inhibitors, such as ADX-629; adenosine receptor agonists, such as CF-102 (namodenoson), CF-101, CF-502, or CGS21680; adiponectin receptor agonists, such as ADP-355 or ADP-399; amylin/calcitonin receptor agonists, such as KBP-042 or KBP-089; AMP-activated protein kinase stimulators, such as PXL-770 or O-304; AMP kinase activators/ATP citrate lyase inhibitors, such as bempedoic acid (ETC-1002, ESP-55016); AMP-activated protein kinase/endothelial nitric oxide synthase/NAD-dependent deacetylase longevity protein-1 stimulators, such as NS-0200 (leucine + metformin + sildenafil); androgen receptor agonists, such as LPCN-1144; angiotensin II AT-1 receptor antagonists, such as irbesartan; angiopoietin-associated protein-3 inhibitors, such as IONIS-ANGPTL3-LRx; autocrine motor factor inhibitors, such as PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, AM-063, or BBT-877; Axl tyrosine kinase receptor inhibitors, such as bemcentinib (BGB-324, R-428); Bax protein stimulators, such as CBL-514; Bioactive lipids, such as DS-102; Cannabinoid receptor type 1 (CNR1) inhibitors, such as namacizumab, GWP-42004, REV-200 or CRB-4001; Apoptotic protease inhibitors, such as emricasan; Pan cathepsin B inhibitors, such as VBY-376; Pan cathepsin inhibitors, such as VBY-825; CCR2/CCR5 chemotherapeutic hormone antagonists, such as cenicriviroc, maraviroc, CCX-872 or WXSH-0213; CCR2 chemotherapeutic hormone antagonists, such as propagermanium; CCR2 chemotherapeutic hormone/angiotensin II AT-1 receptor antagonists, such as DMX-200 or DMX-250; CCR2/CCR5 chemotherapeutic hormone antagonists and FXR agonists, such as LJC-242 (tropifexor + cenivriviroc); CCR3 chemotherapeutic hormone antagonists, such as bertilimumab; Chloride channel stimulators, such as cobiprostone or lubiprostone; CD3 antagonists, such as NI-0401 (foralumab); CXCR4 chemokine antagonists, such as AD-214; diglycerol acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356; diglycerol O-acyltransferase 1 (DGAT1)/cytochrome P450 2E1 inhibitors (CYP2E1), such as SNP-610; diglycerol acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx or PF-06865571; Dipeptidyl peptidase IV inhibitors, such as linagliptin or evogliptin; Eosin ligand inhibitors, such as bacitrazumab or CM-101; Extracellular matrix protein regulators, such as CNX-024; Farnesoid X receptor (FXR) agonists, such as AGN-242266, AGN-242256, EP-024297, RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, GS-9674, LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M-480, MET-409, PX20606, EYP-001, TERN-101, TC-100, INT-2228; Farnesoid X receptor (FXR)/G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767; Fatty acid synthase inhibitors, such as TVB-2640; FGF receptor agonists/clotrol beta stimulators, such as BFKB-8488A (RG-7992); Fibroblast growth factor 19 (rhFGF19)/cytochrome P450 (CYP) 7A1 inhibitors, such as NGM-282; Fibroblast growth factor 21 (FGF-21) ligands, such as BMS-986171, BIO89-100, B-1344, or BMS-986036; Fibroblast growth factor 21 (FGF-21)/glucagon-like peptide 1 (GLP-1) agonists, such as YH-25723 (YH-25724; YH-22241) or AKR-001; Fish oil compositions, such as eicosapentaenoic acid ethyl ester (Vascepa ^® ); Galectin-3 inhibitors, such as GR-MD-02, GB-1107 (Gal-300) or GB1211 (Gal-400); Glucagon-like peptide 1 receptor (GLP1R) agonists, such as AC-3174, liraglutide, cofactor (MEDI-0382), exenatide, SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718 or semaglutide; Glucocorticoid receptor antagonists, such as CORT-118335 (miricorilant); Glucose 6-phosphate 1-dehydrogenase inhibitors, such as ST001; G protein-coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009 or INT-777; Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201; HMG CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin; Hypoxia-inducing factor-2α inhibitors, such as PT-2567; IL-10 agonists, such as peg-ilodecakin; Ileal sodium bile acid symporter inhibitors, such as odevixibat (A-4250), volixibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, or eloxibat (A-3309); Insulin sensitizers, such as KBP-042, MSDC-0602K, MSDC-5514, Px-102, RG-125 (AZD4076), VVP-100X, CB-4211, or ETI-101; Insulin ligands/insulin receptor agonists, such as ORMD-0801; Integrin antagonists, such as IDL-2965; IL-6 receptor agonists, such as KM-2702; Ketokinase (KHK) inhibitors, such as PF-06835919; β-Clark (KLB)-FGF1c agonists, such as MK-3655 (NGM-313); 5-lipoxygenase inhibitors, such as tipelukast (MN-001), DS-102 (AF-102); Lipoprotein lipase inhibitors, such as CAT-2003; LPL gene stimulators, such as alipogene tiparvovec; Liver X receptor (LXR) modulators, such as PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, or SR-9238; Lysophosphatidic acid-1 receptor antagonists, such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, or KI-16198; Lysamidyl oxidase homolog 2 inhibitors, such as simtuzumab or PXS-5382A (PXS-5338); Macrophage mannose receptor 1 modulators, such as tilmanocept-Cy3 (Tc 99m temanothi); membrane copper amine oxidase (VAP-1) inhibitors, such as TERN-201; MEKK-5 protein kinase (ASK-1) inhibitors, such as GS-4997, SRT-015 or GS-444217, GST-HG-151; MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158); methionine aminopeptidase-2 inhibitors, such as ZGN-839, ZGN-839 or ZN-1345; methyl CpG binding protein 2 regulators, such as ethylamine; mitochondrial decoupling agents, such as 2,4-dinitrophenol or HU6; Mixed spectrum kinase-3 inhibitors, such as URMC-099-C; Myelin alkaline protein stimulators, such as olesoxime; NADPH oxidase 1/4 inhibitors, such as GKT-831 or APX-311; Niacin receptor 1 agonists, such as ARI-3037MO; Nitazoxinide; NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514, or JT-194 (JT-349); Nuclear receptor modulators, such as DUR-928 (DV-928); P2X7 purine receptor modulators, such as SGM-1019; P2Y13 purine receptor stimulators, such as CER-209; PDE 3/4 inhibitors, such as Taluster (MN-001); PDE 5 inhibitors, such as sildenafil or MSTM-102; PDGF receptor β modulators, such as BOT-191 or BOT-509; Peptidyl-prolinyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018 or NV-556 (NVP-025); Phenylalanine hydroxylase stimulators, such as HepaStem; PPAR agonists (including PPAR α agonists, PPAR α/δ agonists, PPAR α/δ/γ agonists, PPAR δ agonists), such as elafibranor (GFT-505), MBX-8025, deuterated pioglitazone R-enantiomer, pioglitazone, DRX-065, saroglitazar, or IVA-337; PPAR α agonists, such as aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, pemafibrate, ronifibrate, simfibrate, omega-3 fatty acids (fish oils, such as eicosapent ethyl (Vascepa ^® ) or docosahexaenoic acid), pirinixic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, muraglitzar, or saxaglitazar; PPAR alpha/delta agonists, such as elafinor; PPAR α/δ/γ agonists, such as lanifenor; PPAR δ agonists, such as seladelpar; Protease-activated receptor-2 antagonists, such as PZ-235; Protein kinase modulators, such as CNX-014; Rho-related protein kinase (ROCK) inhibitors, such as REDX-10178 (REDX-10325) or KD-025; Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) inhibitors, such as PXS-4728A; S-nitroglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891; Sodium glucose transporter-2 (SGLT2) inhibitors, such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, or sotagliflozin; SREBP transcription factor inhibitors, such as CAT-2003 or MDV-4463; Stearoyl CoA desaturase-1 inhibitors, such as aramchol; Thyroid hormone receptor (THR) beta agonists, such as rismond (MGL-3196), MGL-3745, or VK-2809; TLR-2/TLR-4 antagonists, such as VB-201 (CI-201); TLR-4 antagonists, such as JKB-121; tyrosine kinase receptor modulators, such as CNX-025 or GFE-2137 (repurposed nitazoxanide); GPCR modulators, such as CNX-023; nuclear hormone receptor modulators, such as Px-102; xanthine oxidase/urate anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001, RLBN-1127; and zonulin inhibitors, such as lorazotide acetate (INN-202).

Additional non-limiting examples of one or more additional therapeutic agents include: ACE inhibitors, such as benazepril, imidapril; Adenosine A3 receptor antagonists, such as FM-101; Adropin stimulants, such as RBT-2; Albumin regulators, such as SYNT-002; Aldosterone/corticosteroid receptor antagonists, such as M T-3995; Allogeneic bone marrow-derived mesenchymal cell therapy, such as ORBCEL-M; Allogeneic expanded adipose-derived stem cell therapy, such as Elixcyte™; AMP-activated protein kinase stimulators/proprotein convertase PC9 inhibitors, such as O-304; AMP-activated protein kinase stimulators, such as DZCY-01, MK-8722, PXL-770; Angiotensin II AT-1 receptor/CCR2 chemokine antagonists, such as DMX-200; Angiotensin II AT-2 receptor agonists, such as MOR-107, irbesartan; Angiotensin II receptor antagonists, such as losartan; Angiotensin proligand inhibitors, such as ALN-AGT; Anti-C1 antibodies, such as BIVV-009 (sutimlimab); Anti-CB1 antibodies, such as GFB-024; Anti-CX3CR1 nanoantibodies, such as BI-655088; Anti-IL-6 antibodies, such as COR-001; Anti-VEGF-B antibodies, such as CSL-346; APOA1 gene stimulators/bromodomain-containing protein 2/bromodomain-containing protein 4 inhibitors, such as apabetalone; Bone morphogenetic protein-7 ligand regulators, such as BMP-7; Calcium channel inhibitors, such as TBN (xiaotongqin); Cannabinoid CB1 receptor antagonists, such as JNJ-2463; CB1 reverse agonists, such as CRB-4001; Chonomycin inhibitors, such as fulacimstat (BAY-1142524); Cyclooxygenase 1 inhibitors, such as GLY-230; Cyclooxygenase 2/epoxide hydrolase inhibitors, such as COX-2/soluble epoxide hydrolase; Cytochrome P450 11B2 inhibitors, such as aldosterone synthase inhibitors; Exonucleotide pyrophosphatase-PDE-2 inhibitors, such as BLD-0409; Endothelin ET-A/endothelin ET-B receptor antagonists, such as aprocitentan; Enteropepeptidase inhibitors, such as SCO-792; Erythropoietin receptor antagonists, such as EPO-018B; Farnesoid X receptor agonists, such as LMB-763; FGF/PDGF/β receptor antagonists/p38 MAP kinase inhibitors, such as pirfenidone; GHR/IGF1 gene inhibitors, such as atesidorsen sodium sodium); GPR40 agonists/GPR84 antagonists, such as PBI-4050; G protein β subunit inhibitors, such as galleon; G protein-coupled receptor 84 modulators, such as PBI-4425; Growth hormone ligands/Growth hormone receptor agonists, such as Jintropin AQ™; Growth hormone receptor agonists, such as LAT-8881; Guanylate cyclase receptor agonists/Guanylate cyclase stimulators, such as praliciguat; Guanylate cyclase stimulators, such as MRL-001, runcaciguat; Hydrogen stromal oxygenase 1 modulators, Such as RBT-1; HIF prolinyl hydroxylase inhibitors, such as TRGX-154; Insulin sensitizers/kinin release 1 modulators, such as DM-199; Integrin α-V/β-3 antagonists, such as VPI-2690B; Interleukin 33 ligand inhibitors, such as MEDI-3506; Kelch-like ECH-related protein 1 regulator/erythroid lineage 2-related factor 2 stimulator, such as SFX-01; LDHA gene inhibitor, such as nedosiran; 5-lipoxygenase activating protein inhibitor, such as AZD-5718; Lysophosphatidic acid-1 receptor antagonist, such as BMS-002, EPGN-696; Matrix extracellular phosphatidylcholine regulator/phosphatonin receptor agonist, such as TPX-200; MEKK-5 protein kinase inhibitor, such as selonsertib; Membrane copper amine oxidase inhibitor, such as UD-014; Mesophase factor =Subligand inhibitors, such as CAB-101; Oligocortin receptor antagonists, such as AZD-9977, esaxerenone, finerenone, KBP-5074; Myosin 2 inhibitors, such as DeciMab™; NADPH oxidase 1 inhibitors/NADPH oxidase 4 inhibitors, such as setanaxib; NADPH oxidase inhibitors, such as APX-115; NK1 receptor antagonists/opioid receptor κ agonists/opioid receptor μ antagonists, such as AV-104; TGF-β2 stimulators β-ligand inhibitors, such as CU01-1001; Nuclear factor κB inhibitors, such as mefunidone, bardoxolone methyl (NSC-713200); PDE 4 inhibitors, such as ART-648, PCS-499; PDGF receptor β-modulators, such as BOT-191; PDGF/VEGF receptor antagonists, such as ANG-3070; PR84 antagonists/GPR40 (FFAR1)/GPR120 (FFAR4) agonists/and partial activators of peroxisome proliferator-activated receptors (PPAR), such as PBI-4547; PRKAA2 gene stimulators/AMPK activators, such as PF-06679142, PF-06685249; Prostacyclin (PGI2) agonists, such as YS-1402; Protein C activators/glycoprotein Ib (GPIb) antagonists, such as AB-002; Protein NOV homolog regulators, such as BLR-200; Protein tyrosine phosphatase-1B inhibitors, such as MSI-1436; Reactive oxygen species regulator inhibitors, such as SUL-121; Nephrin inhibitors, such as imarikiren hydrochloride; Rho-related protein kinase 2 inhibitors, such as ANG-4201, RXC-007; Sodium glucose transporter-2 inhibitors, such as canagliflozin, dapagliflozin propylene glycol, empagliflozin; Thrombin A2 receptor antagonists/thrombin Tissue transglutaminase inhibitors, such as ZED-1227; TRP cation channel C5 inhibitors, such as GFB-887; TRP cation channel C6 inhibitors, such as ALGX-2224; Cell adhesion molecule inhibitors, such as glycosidic bacterial adhesin antagonists; Urate anion exchanger 1 (URAT1)/SLC22A12 inhibitors, such as verinurad (RDEA3170); VIP 1/VIP 2 receptor agonists, such as LBT-3627; and Xanthine oxidase inhibitors, such as TMX-049, TMX-049DN.

In some embodiments, the one or more additional therapeutic agents are selected from A-4250, AC-3174, acetylsalicylic acid, AK-20, alipoquinone, AMX-342, AN-3015, alemiro, ARI-3037MO, aspartate-8232, AZD-2693, betilimumab, anhydrous betaine, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, B TT-1023, CAT-2003, Senivero, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, coprestone, colesevelam, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, Eraphinol (GFT-505), Enricasan, Enalapril, Eragliptin, Emigliptin, F-351, Fluasterone (ST-002), FT-4101, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, HTD-1801, HST-202, HST-201, Hydrochlorothiazide, Eicosyl ester (PRC-4016), icosapent ethyl, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, ipragliptin, irbesartan, propagation, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide, LJN-452 (Tripiflux), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MBX-8025, MDV-4463, ethylamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, nablizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-160, nordeoxycholic acid, NVP-022, O-304, obeticholic acid (OCA), 25HC3S, olisoxime, PAT-505, PAT-048, PBI-4547, peg-iloleukin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RDX-009, repaglinide etabonate, RG-125 (AZD4076), RPI-500, saroglitazar, semaglutide, simtuzumab, Solisomycin, solafloxacin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), symbiotic, TCM-606F, TEV-45478, TQA-3526, telust (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, vismodegib, volixibat potassium ethanolate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, XRx-117, ZGN-839, ZG-5216, ZSYM-008 and ZYSM-007.

In some embodiments, the methods and pharmaceutical compositions provided herein include a therapeutically effective amount of an apoptosis signal-regulating kinase 1 (ASK1) inhibitor and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi) provided herein, or a pharmaceutically acceptable salt thereof.

In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ASK1 inhibitor is GS-4997 (selonsertib, SEL).

ASK1 inhibitors can be synthesized and characterized using methods known to those skilled in the art, such as those described in U.S. 2007/0276050, U.S. 2011/0009410, and U.S. 2013/0197037.

In some embodiments, the methods and pharmaceutical compositions provided herein include a therapeutically effective amount of an acetyl-CoA carboxylase (ACC) inhibitor and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi) provided herein, or a pharmaceutically acceptable salt thereof.

In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ACC inhibitor is GS-0976 (fisocostat, FIR).

ACC inhibitors can be synthesized and characterized using methods known to those skilled in the art, such as those described in U.S. Patent No. 9,453,026 and U.S. Patent No. 10,183,951.

In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of a PPAR agonist (e.g., a PPAR α agonist, a PPAR α/δ agonist, a PPAR α/δ/γ agonist, a PPAR δ agonist) or fish oil, a therapeutically effective amount of an acetyl CoA carboxylase (ACC) inhibitor, such as GS-0976 (fisocostat, FIR), and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the PPAR agonist is a PPAR alpha agonist. In some embodiments, the PPAR alpha agonist is selected from: aluminum clofibrate, benzafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clobemide, fenofibrate, gemfibrozil, permafibrate, clofibrate, bifibrate, pironic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitza, mulaglitza and saxaglitza. In some embodiments, the PPAR agonist (e.g., PPAR alpha agonist) is a fibrate. In some embodiments, the PPAR agonist (e.g., a PPAR alpha agonist) is fenofibrate. In some embodiments, the PPAR agonist is a PPAR alpha/delta agonist (e.g., elafinol). In some embodiments, the PPAR agonist is a PPAR alpha/delta/gamma agonist (e.g., lanifino). In some embodiments, the PPAR agonist is a PPAR delta agonist (e.g., seradepa). In some embodiments, the fish oil is omega-3 fatty acids or docosahexaenoic acid. In some embodiments, the fish oil is eicosapentaenoic acid ethyl ester (e.g., Vascepa ^® ).

In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of a farnesoid X receptor (FXR) agonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) provided herein, or a pharmaceutically acceptable salt thereof.

In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is GS-9674 (cilofexor, CILO).

In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is a compound having the following structure: or a pharmaceutically acceptable salt thereof.

In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of a GLP-1 receptor agonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is liraglutide or semaglutide. In some embodiments, the GLP-1 receptor agonist is semaglutide.

In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of a TGFβ antagonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn) or (IIo) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the TGFβ antagonist is a TGFβ specific antibody. TGFβ specific antibodies can be prepared and characterized using methods known to those skilled in the art, such as those described in PCT International Application Publication No. WO 2018/129329 and U.S. Patent No. 9,518,112. In some embodiments, the TGFβ antagonist binds to a TGFβ latent associated peptide (LAP), such as TGFβ 1-LAP. TGFβ 1-LAP specific antibodies can be prepared and characterized using methods known to those skilled in the art, such as those described in U.S. Patent No. 8,198,412 or U.S. Patent No. 10,017,567. In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ 1) in a context-independent manner (e.g., independent of the presentation of TGFβ in a particular tissue or organ). In some embodiments, the TGFβ antagonist binds to TGFβ (TGFβ 1) in a context-dependent manner. In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ 1) located in the extracellular matrix (e.g., in the connective tissue of the liver). In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ 1) located in the thymus, lymph nodes, or tumor microenvironment (e.g., in patients with liver cancer). In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ 1) by latent TGFβ binding protein (LTBP). In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ 1) by glycoprotein-A repeat prioritization protein (GARP), as described, for example, in U.S. Patent No. 10,000,572. In some embodiments, the TGFβ antagonist is ARGX-115. In some embodiments, the TGFβ antagonist is an anti-latency associated peptide (LAP) antibody that specifically binds to a LAP-TGFβ complex. In some embodiments, the anti-LAP antibody specifically binds to a LAP-TGFβ complex in the extracellular matrix (ECM) of connective tissue, for example, in the liver. In some embodiments, the anti-LAP antibody specifically binds to a LAP-TGFβ complex, for example, on the surface of certain immunosuppressive cell types, such as regulatory T cells (Treg), tumor-associated macrophages, or bone marrow-derived suppressor cells in the tumor microenvironment. In some embodiments, the anti-LAP antibody is a TLS-01 antibody. In some embodiments, the anti-LAP antibody specifically binds to a LAP-TGFβ complex under any circumstances. In some embodiments, the anti-LAP antibody is a TLS-02 antibody. In some embodiments, the TGFβ antagonist comprises a TGFβ receptor. In some embodiments, the TGFβ antagonist is a TGFβ receptor-Fc fusion protein. In some embodiments, the TGFβ antagonist is an antibody comprising a TGFβ receptor. TGFβ antagonists comprising a TGFβ receptor that can be used in conjunction with the compositions and methods provided herein have been described, for example, in PCT International Publication Nos. WO 2019/113123 A1 and WO 2019/113464 A1.

In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an ACE inhibitor, an adenosine A3 receptor antagonist, an adrenopine stimulator, an albumin regulator, an aldosterone antagonist, an AMP-activated protein kinase stimulator, an vasopressin II AT-2 receptor agonists, vasopressin II receptor antagonists, vasopressin ligand inhibitors, APOA1 gene stimulators, apolipoprotein L1 regulators, bone morphogenetic protein-7 ligand regulators, bromodomain-containing protein 2 inhibitors, bromodomain-containing protein 4 inhibitors, calcium channel inhibitors, cannabinoid CB1 receptor antagonists, CB1 reverse agonists, CCR2 chemokine antagonists, rennet inhibitors, complement C1 subcomponent inhibitors, CX3CR1 chemokine antagonists, cyclooxygenase 1 inhibitors, cyclooxygenase 2 inhibitors, cytochrome P450 11B2 inhibitors, ectonucleotide pyrophosphatase-PDE-2 inhibitors, endothelin ET-A receptor antagonists, endothelin ET-B receptor antagonists, enteropeptidase inhibitors, epoxide hydrolase inhibitors, erythropoietin receptor antagonists, farnesoid X receptor agonists, FGF receptor antagonists, free fatty acid receptor 1 agonists, GHR gene inhibitors, glycoprotein Ib (GPIb) antagonist, GPR40 agonist, GPR84 antagonist, G protein β subunit inhibitor, G protein coupled receptor 120 agonist, G protein coupled receptor 84 modulator, growth hormone ligand, growth hormone receptor agonist, guanylate cyclase receptor agonist, guanylate cyclase stimulator, blood matrix oxygenase 1 regulator, HIF prolinyl hydroxylase inhibitor, IGF1 gene inhibitor, IgG receptor FcRn large subunit p51 regulator, IL-6 receptor antagonist, integrin α-V/β-3 antagonist, interleukin 33 ligand inhibitor, Kelch-like ECH-related protein 1 regulator, LDHA gene inhibitor, 5-lipoxygenase activating protein inhibitor, lysophosphatidic acid-1 receptor antagonist, extracellular phosphoglycoprotein regulator, membrane copper amine oxidase inhibitor, midkine ligand inhibitor, halocorticoid hormone receptor antagonist, myosin 2 inhibitor, NADPH oxidase 1 inhibitor, NADPH oxidase 4 inhibitor, NADPH oxidase inhibitor, NK1 receptor antagonist, nuclear erythroid lineage 2-related factor 2 stimulator, nuclear factor κ B inhibitor, opium receptor κ agonist, opium receptor μ antagonist, p38 MAP kinase inhibitors, PDE4 inhibitors, PDGF receptor antagonists, PDGF receptor β regulators, phospho-regulator receptor agonists, PRKAA2 gene stimulators, proprotein convertase PC9 inhibitors, prostaglandin (PGI2) agonists, protein C activators, protein NOV homolog regulators, protein tyrosine phosphatase-1B inhibitors, reactive oxygen species regulator inhibitors, renin inhibitors, rho-related protein kinase 2 inhibitors, SLC22A12 inhibitors , sodium glucose transporter-2 inhibitors, solute carrier family inhibitors, TGFβ ligand inhibitors, TGFβ receptor antagonists, thrombin A2 receptor antagonists, thrombin synthesis inhibitors, tissue transglutaminase inhibitors, TRP cation channel C5 inhibitors, TRP cation channel C6 inhibitors, tryptophanase inhibitors, non-specific cell adhesion molecules, urate anion exchanger 1 inhibitors, vasopressin V1a receptor antagonists, VEGF receptor antagonists, VIP 1 receptor agonists, VIP 2 receptor agonists and xanthine oxidase inhibitors.

In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of a VEGFR inhibitor, a FGFR inhibitor, a PDGFR inhibitor, an autaxin inhibitor, a GPR84 agonist, a PASK inhibitor, a CFTR agonist, a JAK1 inhibitor, an ADAMTS5 inhibitor, a TOL2/3 inhibitor, a CTGF inhibitor, a soluble PTX2, an anti-galectin-3 antibody, an integrin-α _V -β ₆ /α _V -β ₁ antagonists, JNK1 inhibitors, alkaloid receptor antagonists, Nrf2 activators, chymosin inhibitors, PDE inhibitors, NOX1/4 inhibitors, leukotriene/thrombin receptor antagonists, SLC22A12 inhibitors, sGC inhibitors and xanthine oxidase inhibitors.

In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of nintedanib, pirfenidone, pamrevlumab, PRM-151, GB-0139, PLN-74809, CC-90001, feretinol, BAY1142524, PCS-499, sitanacoxib, SER150, RDEA3170, pariciquine, TMX-049, GLPG1690, GLPG1205, GLPG1972, GLPG4059, GLPG2737, GLPG3970, and filgotinib.

In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of A-717, ACF-TEI, alanyl-glutamine, ALLN-346, anti-SCF248 antibody, anti-TAGE monoclonal antibody, anti-TGF β antibody, AST-120, BAY-2327949, BI-685509, DP-001, DZ-4001, GDT-01, LNP-1892, MEDI-8367, antisense oligonucleotide therapy targeting microRNA, MK-2060, MPC-300-IV, NAV-003, Neo-Kidney Augment™ (NKA), NP-135, NP-160, NP-251, NRF-803, PBI-4610, PHN-033, R-HSC-010, salvianolic acid, SGF-3, SPD-01, Sugarheal variants , SZ-005, TCF-12, UMC119-06, VAR-400, veverimer, VS-105, and XRx-221.

The following examples are included to demonstrate specific embodiments of the present invention. Those skilled in the art will appreciate that the techniques disclosed in the following examples represent techniques that work well in practicing the present invention, and therefore may be considered to constitute specific modes of its practice. However, in view of the present invention, those skilled in the art will appreciate that these examples are illustrative and non-exhaustive. Many changes may be made in the specific embodiments disclosed and still obtain similar or similar results without departing from the spirit and scope of the present invention.

The compounds disclosed herein can be prepared using appropriate materials according to the procedures of the following flows and examples, and are further illustrated by the following specific examples. In addition, by utilizing the procedures described herein, combined with the general skills in this technology, additional compounds of the present invention claimed herein can be easily prepared. The examples further illustrate the details of preparing the compounds of the present invention. Those skilled in the art will readily understand that the conditions of the following preparation procedures and known variations of the processes can be used to prepare these compounds. To synthesize compounds as embodiments described in the present invention, inspection of the structure of the compound to be synthesized will provide identification of each substituent. In some cases, the consistency of the final product can make the consistency of the necessary starting materials apparent by the process of inspection, giving the examples herein. The compound can be isolated in the form of its pharmaceutically acceptable salt (such as those described above). The compounds described herein are generally stable and isolatable at room temperature and pressure.

The following is a description of the preparation of the compounds disclosed herein. Unless otherwise specified, the variables have the same meanings as described above. The examples presented below are intended to illustrate specific embodiments of the present invention. Suitable starting materials, building blocks and reagents used in the syntheses described below are commercially available from, for example, AbovChem, Acros Organics, Astatech, Combi Blocks, Oakwood Chemical or Sigma-Aldrich, or can be routinely prepared by procedures described in the literature (e.g., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition; John Wiley & Sons or T. Eicher, S. Hauptmann, The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application, 2nd edition, Wiley-VCH 2003; Fieser et al., Fiesers' Reagents for Organic Synthesis, John Wiley & Sons 2000). General Schemes Scheme A

Scheme A provides a general synthesis of triazole aryl and heteroaryl carbamates ( VI ). In the schemes disclosed herein, "A" can be a halogen, such as Cl, Br or I. Aryl or heteroaryl halides (I) can be readily prepared by electrophilic aromatic halogenation of the corresponding aryl or heteroaryl amines. Acylation of aryl and heteroaryl amines ( I ) is described in step 1. Amines ( I ) can be treated with acyl chlorides or carboxylic acids using standard peptide coupling conditions, such as using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), to give the corresponding amides ( II ). Alternatively, amines ( I ) can also be treated with chloroformates to give the corresponding carbamates ( II ). Alternatively, the amine ( I ) can be first treated with phosgene to produce an intermediate isocyanate, which can then be captured by the amine to give the corresponding urea ( II ).

Step 2 describes the general synthesis of aryl or heteroaryl triazole carboxylic acids ( IV ) via cross-coupling reactions. The aryl or heteroaryl halide ( II ) can first be converted to a pinacol via Miyura borylation. Ester Correspondence The ester is then subjected to Suzuki reaction conditions with bromotriazole carboxylic acid ( III ) to afford the desired aryl or heteroaryl triazole carboxylic acid ( IV ). Alternatively, bromotriazole carboxylic acid ( III ) can first be converted to an organozinc species via lithium-halide exchange and captured with zinc chloride. Next, Negishi cross coupling with aryl or heteroaryl halide ( II ) affords the desired aryl or heteroaryl triazole carboxylic acid ( IV ).

Step three describes the general synthesis of triazole aryl and heteroaryl carbamates ( VI ). The aryl or heteroaryl triazole carboxylic acid ( IV ) undergoes a Curtius rearrangement when treated with diphenylphosphatidyl aziride (DPPA) or alternatively with 1-propanephosphonic anhydride (T3P) solution and trimethylsilane aziride. The intermediate isocyanate is subsequently captured with an alcohol ( V ) to give the desired aryl or heteroaryl triazole carbamate ( VI ). Scheme B

Scheme B provides an alternative synthesis of triazole aryl and heteroaryl carbamates (VI). Step 1 describes the general synthesis of aminoaryl or heteroaryl triazole carbamates ( XI ) via a cross-coupling reaction. The bromotriazole carbamate ( X ) can first be converted to an organozinc species via lithium-halide exchange and captured with zinc chloride. Next, cross-coupling with an aryl or heteroaryl halide ( I ) affords the desired aminoaryl or heteroaryl triazole carbamate ( XI ). Alternatively, the aryl or heteroaryl halide (I) can first be converted to a pinacol such as via Miyaura borylation. Ester Correspondence The ester is then reacted with bromotriazole carbamate ( X ) under Suzuki reaction conditions to obtain the desired aminoaryl or heteroaryl triazole carbamate ( XI ).

Step 1A-B Description Alternative synthesis of aminoaryl or heteroaryl triazole carbamates (XI). Tributyl carbamates ( XII ) can be readily prepared by treating the corresponding aryl or heteroaryl amine with tributyl dicarbonate. The aryl or heteroaryl halide ( XII ) can first be converted to a pinacol via Miyura borylation. Ester Correspondence esters and subsequently subjected to Suzuki reaction conditions with bromotriazole carbamate ( X ) to afford the desired aminoaryl or heteroaryl triazole carbamate ( XIII ). Alternatively, the bromotriazole carbamate ( X ) can first be converted to an organozinc species via lithium-halide exchange and captured with zinc chloride. Subsequently, Negishi cross-coupling with an aryl or heteroaryl halide ( XII ) affords the desired aryl or heteroaryl triazole carbamate ( XIII ). Next, the tertiary butyl aryl or heteroaryl triazole carbamate ( XIII ) can be treated with an acid such as hydrochloric acid (HCl) to afford the aminoaryl or heteroaryl triazole carbamate ( XI ) in the form of a hydrochloride salt.

Step 2 describes the general synthesis of triazole aryl and heteroaryl carbamates ( VI ). Aminaryl or heteroaryl triazole carbamates ( XI ) can be treated with acyl chlorides or carboxylic acids using standard peptide coupling conditions, such as using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), to give the corresponding amides ( VI ). Alternatively, amines ( XI ) can also be treated with chloroformates to give the corresponding carbamates ( VI ). In addition, amines ( XI ) can first be treated with phosgene to produce the intermediate isocyanate, which can then be captured by the amine to give the corresponding urea ( VI ). Scheme C .

Scheme C provides a general alternative synthesis of aryl or heteroaryl triazole carbamates ( VI ). Step 1 describes the general synthesis of aryl or heteroaryl triazole carboxylic acids ( XIV ) via a cross-coupling reaction. The aryl or heteroaryl halide ( XII ) can first be converted to a pinacol via Miyura borylation. Ester Correspondence The ester is then subjected to Suzuki reaction conditions with bromotriazole carboxylic acid ( III ) to afford the desired aryl or heteroaryl triazole carboxylic acid ( XIV ). Alternatively, bromotriazole carboxylic acid ( III ) can first be converted to an organozinc species via lithium-halide exchange and captured with zinc chloride. Next, Negishi cross coupling with aryl or heteroaryl halide ( XII ) affords the desired aryl or heteroaryl triazole carboxylic acid ( XIV ).

Step two describes the general synthesis of aryl or heteroaryl triazoles containing carbamates ( XIII ). Aryl or heteroaryl triazole carboxylic acids ( XIV ) undergo Curtis rearrangement when treated with diphenylphosphatidyl aziride (DPPA) or alternatively with 1-propanephosphonic anhydride (T3P) solution and trimethylsilane aziride. Subsequent capture of the intermediate isocyanate with an alcohol ( V ) affords the desired aryl or heteroaryl triazole carbamate ( XIII ). Step three describes the general synthesis of aminoaryl or heteroaryl triazole carbamates ( XI ). The tertiary butyl aryl or heteroaryl carbamate ( XIII ) can be treated with an acid such as hydrochloric acid (HCl) to afford the aminoaryl or heteroaryl triazole carbamate ( XI ) in the form of a hydrochloride salt.

Step 4 describes the general synthesis of triazole aryl and heteroaryl carbamates ( VI ). Aminaryl or heteroaryl triazole carbamates ( XI ) can be treated with acyl chlorides or carboxylic acids using standard peptide coupling conditions, such as using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), to give the corresponding amides ( VI ). Alternatively, amines ( XI ) can also be treated with chloroformates to give the corresponding carbamates ( VI ). In the case of using phenyl chloroformate, the resulting phenyl carbamate ( VI ) can be treated with an amine to produce the corresponding urea ( VI ). In addition, amines ( XI ) can first be treated with phosgene to produce the intermediate isocyanate, which can then be captured by the amine to give the corresponding urea ( VI ). Scheme D

Scheme D describes an alternative synthesis of triazole carbamate aryl and heteroaryl carboxamides ( VI ). E can be a halogen, such as -Br or -I. In step one, the aryl or heteroaryl dihalide ( XV ) undergoes a sonogaoka coupling with a propargyl alcohol to produce an aryl or heteroaryl-alkyne ( XVI ). The alkyne is then subjected to a thermal or catalytic cycloaddition with an azido compound to produce the corresponding hydroxymethyltriazole (XVII) in step two. Finally, in step three, the primary alcohol is oxidized using tetramethylpiperidinyloxy (TEMPO) and sodium chlorite to give the triazole carboxylic acid ( XVIII ).

In step 4, the triazole carboxylic acid ( XVIII ) is protected as the methyl ester ( XIX ) by treatment with thionyl chloride. In step 5, the aryl or heteroaryl halide ( XIX ) is then subjected to a Buchwald-type amination with tert-butyl carbamate to produce the Boc-protected amine ( XX ).

In step six, the Boc-protected amine ( XX ) is exposed to hydrochloric acid to reveal the hydrochloride ( XXI ), which can be reacted in step seven with an acyl chloride or carboxylic acid using standard peptide coupling conditions, such as using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), to give the corresponding amide ( XXII ). Alternatively, the amine ( XXI ) can also be treated with a chloroformate to give the corresponding carbamate ( XXII ). In addition, the amine ( XXI ) can first be treated with phosgene to produce an intermediate isocyanate, which can then be captured by the amine to give the corresponding urea ( XXII ). In step eight, the triazole ester ( XXII ) can be hydrolyzed upon treatment with a base such as sodium hydroxide to reveal the triazole carboxylic acid ( IV ). Finally, step nine describes the Curtis rearrangement of the triazole carboxylic acid ( IV ) via treatment with diphenylphosphatidyl azide (DPPA) or with 1-propanephosphonic anhydride (T3P) solution and trimethylsilane azide. The intermediate isocyanate is then captured with an alcohol ( V ) to give the desired aryl- or heteroaryl-triazole carbamate ( VI ). Example 1 : Preparation of 4- bromo -1- methyl -1H-1,2,3 - triazole -5- carboxylic acid ( Intermediate 1) Step 1 : 4,5- dibromo -2H-1,2,3 -triazole

Bromine (2.8 mol) was added to a solution of 2H-1,2,3-triazole (1.4 mol) in water (600 mL) at 40°C. The resulting mixture was stirred at 40°C for 2 hours. After cooling to room temperature, the precipitate was collected by filtration. The solid was washed with water (2 × 300 mL) and dried under vacuum to give 4,5-dibromo-2H-1,2,3-triazole. Step 2 : 4,5- Dibromo -1- methyl -1H-1,2,3- triazole

To a mixture of 4,5-dibromo-2H-1,2,3-triazole (704 mmol) and K ₂ CO ₃ (1.4 mol) in THF (1000 mL) was added iodomethane (1.0 mol). The mixture was stirred at room temperature for 12 hours. The mixture was filtered and the filter cake was washed with ethyl acetate (2×500 mL), the filtrate was concentrated at 40°C to give a crude product, which was purified by column chromatography to give 4,5-dibromo-1-methyl-1H-1,2,3-triazole. Step 3 : 4 - Bromo - 1- methyl -1H-1,2,3- triazole -5- carbaldehyde

To a solution of 4,5-dibromo-1-methyl-1H-1,2,3-triazole (168.0 mmol) in THF (600 mL) at -10 °C was added isopropylmagnesium chloride (252.0 mmol). The mixture was stirred for 15 min and DMF (840 mmol) was added. After 1 h, the mixture was treated with 250 mL of saturated ammonium chloride and extracted with DCM (2 x 350 mL). The combined organics were washed with 250 mL of brine, dried _{over Na2SO4} , filtered and concentrated to give 4-bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde. Step 4 : 4- Bromo -1- methyl -1H-1,2,3- triazole -5- carboxylic acid

Potassium hydrogen persulfate (651 mmol) was added to a solution of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde (536 mmol) in DMF (800 mL) and the resulting suspension was stirred at room temperature overnight. The mixture reaction was diluted with H ₂ O (1000 mL), adjusted to pH 3 with 1N HCl, and the aqueous phase was extracted with ethyl acetate (3×800 mL). The combined organics were washed with saturated Na ₂ CO ₃ (2×500 mL), and the aqueous phase was adjusted to pH 3 with 1N HCl. The precipitate was separated by filtration and dried under reduced pressure to give 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1). Example 2 : Preparation of (R)-(4- bromo -1- methyl -1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2- chlorophenyl ) ethyl ester ( Intermediate 2A)

To a suspension of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (24.3 mmol) in toluene (80 mL) were added DPPA (24.5 mmol), triethylamine (24.5 mmol) and (R)-1-(2-chlorophenyl)ethan-1-ol (36.5 mmol). The mixture was heated at 80 °C for 3 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica chromatography to give (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A). Example 3 : Preparation of (R)-(4- bromo -1- methyl -1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Intermediate 2B)

4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (95 mmol), 50% 1-propanephosphonic anhydride solution (143 mmol) and trimethylsilane (143 mmol) in DMF were suspended in THF (350 mL) under an argon atmosphere. Triethylamine (143 mmol) was added and the resulting solution was stirred for 30 minutes. (R)-1-(2-chloropyridin-3-yl)ethan-1-ol (143 mmol) was added and the mixture was heated at reflux with a secondary bubbler attached to allow aeration for 12 hours. The reaction mixture was cooled to room temperature and the THF was removed in vacuo. The resulting crude material was dissolved in 500 mL of ethyl acetate and extracted three times with 300 mL of water. The crude mixture was then dried over sodium sulfate, filtered and the filtrate was concentrated. The crude material was purified by silica gel column chromatography to give (R)-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester (Intermediate 2B). Example 4 : Preparation of (R)-(4- bromo -1- methyl -1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2- fluoropyridin -3- yl ) ethyl ester ( Intermediate 2C)

Following the procedure described in Example 3 for the synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B), using (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (143 mmol) instead of (R)-1-(2-chloropyridin-3-yl)ethan-1-ol, (R)-1-(2-fluoropyridin-3-yl)ethyl (4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2C) was obtained. Example 5: Preparation of 1-(3-fluorophenyl)ethyl (4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2D)

Following the procedure described in Example 3 for the synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B), using (R)-1-(3-fluorophenyl)ethan-1-ol (230 mmol) instead of (R)-1-(2-chloropyridin-3-yl)ethan-1-ol, (R)-1-(3-fluorophenyl)ethyl (4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2D) was obtained. Example 6 : Preparation of methyl 4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylate ( Intermediate 3A)

Intermediate 3A is generally prepared according to Scheme D. Step 1 : 3-(5- bromopyridin -2- yl ) prop -2- yn -1- ol

To a mixture of 5-bromo-2-iodopyridine (352.2 mmol) in THF (400 mL) were added compound prop-2-yn-1-ol (370 mmol), triethylamine (1.06 mol), cuprous iodide (17.6 mmol) and bis(triphenylphosphine)palladium(II) chloride (10.6 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was diluted with water (500 ml) and the solid was filtered. The filtrate was extracted with ethyl acetate (3 × 500 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with ethyl acetate and diethyl ether and stirred for 2 hours and filtered. The filter cake was washed with ether to give 3-(5-bromopyridin-2-yl)prop-2-yn-1-ol. Step 2 : (4-(5- bromopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) methanol

Cuprous iodide (0.94 mmol) and tetrabutylammonium iodide (0.94 mmol) were mixed together and dissolved in THF (30 mL), stirred for 20 minutes to give a solution. Then, 3-(5-bromo-2-pyridyl)prop-2-yn-1-ol (9.43 mmol) was added and the reaction was bubbled with hydrogen for 2 minutes. Pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium(II) chloride (0.47 mmol) and azidomethyltrimethylsilane (24 mmol) were added and the reaction was sealed and heated to 80°C for 16 hours. The reaction mixture was concentrated in vacuo and then redissolved in THF (50 mL). Tetrabutylammonium fluoride (10 mL of 1 M solution in THF) was added dropwise at room temperature and stirred for 1 hour. The mixture was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with DCM (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol. Step 3 : 4-(5- bromopyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid

[5-(5-Bromo-2-pyridinyl)-3-methyl-triazol-4-yl]methanol (4.83 mmol), 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) (0.48 mmol) and sodium dihydrogen phosphate (12.08 mmol) were suspended in acetonitrile (50 ml) and water (40 ml). The solution was heated to 45°C. Subsequently, 10 ml of a 1 M aqueous sodium chlorite solution and a separate sodium hypochlorite solution (10 ml of a 0.01 M aqueous solution) were added simultaneously over 1 hour. The reaction was stirred at 45°C for 16 hours. The mixture was cooled to room temperature and concentrated to remove the acetonitrile. The product was filtered and the filter cake was washed with water (2×50 mL) and ether (50 mL) to give 4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid. LCMS M/Z (M+1)=283.1. Step 4 : 4-(5- bromopyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid methyl ester

4-(5-Bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (14.1 mmol) was dissolved in 40 ml of methanol. The solution was cooled to 0°C with an ice bath. Trimethylsilyldiazomethane (18.4 mmol) was added dropwise over 15 min. The ice bath was removed and the reaction was stirred for 5 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give methyl 4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate. Step 5 : 4-(5-(( tert-butyloxycarbonyl ) amino ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid methyl ester

Methyl 4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate (11.1 mmol), tributyl carbamate (33 mmol), cesium carbonate (33 mmol) and Xantphos Pd G3 precatalyst (1.1 mmol) were suspended in dioxane (50 ml). The suspension was bubbled with argon for 10 minutes and then heated to 95°C for 4 hours. After the reaction was completed, the mixture was cooled and diluted with water (100 ml) and extracted with ethyl acetate (2 × 100 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4-(5-((tributyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid methyl ester. Step 6 : 4-(5- aminopyridin -2 - yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid methyl ester hydrochloride ( Intermediate 3A)

To methyl 4-(5-((tert-butyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate (6 mmol) was added 4 M HCl in dioxane (14 mL) and the reaction was vigorously stirred at room temperature for 3 hours. After the reaction was complete, the solution was concentrated in vacuo to give methyl 4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate hydrochloride (Intermediate 3A). Example 7 : Preparation of 4-(5-(( tert-butyloxycarbonyl ) amino ) pyridin -2- yl )-1- methyl -1H-1,2,3 -triazole -5- carboxylic acid ( Intermediate 3B)

4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (50 mmol) was dissolved in 500 mL tetrahydrofuran and immersed in a -78 °C bath for 15 minutes. A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (54 mmol) was added dropwise over 15 minutes. A 2.5 M solution of n-butyllithium (105 mmol) in hexanes was added dropwise over 20 minutes and stirred for an additional hour. A 1.9 M solution of zinc chloride (105 mmol) in 2-methyltetrahydrofuran was added dropwise over 15 minutes. The reaction mixture was allowed to warm to ambient temperature by immersion in a water bath and stirred for 30 minutes. The resulting mixture was bubbled with argon for 10 min, and then tributyl (6-bromopyridin-3-yl)carbamate (50 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 mmol) complexed with dichloromethane were added. The reaction was heated at 75 °C for 3 hours, and then cooled to ambient temperature. The reaction was diluted with 350 mL of 2 M aqueous sodium hydroxide solution and 300 mL of diethyl ether. The aqueous layer was separated, and the organic layer was extracted with 1 M aqueous sodium hydroxide solution (100 mL). The combined aqueous layers were washed with a 1:1 mixture of ethyl acetate and diethyl ether (150 mL × 2). 80 mL of concentrated hydrochloric acid was added dropwise under vigorous stirring within 10 min to adjust the pH to 4. The mixture was filtered, and the filter cake was washed with water (100 mL) and a 1:1 mixture of ethyl acetate and diethyl ether (100 mL × 2). The precipitate was dried under reduced pressure to give 4-(5-((tributyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 3B). Example 8 : Preparation of (R)-1- (3- fluorophenyl )ethyl(1- methyl -4-(4-(2,2,2- trifluoroacetamido ) phenyl )-1H-1,2,3- triazol - 5- yl ) carbamate ( Compound 1 ) Step 1 : (R)-(4-(4- aminophenyl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(3- fluorophenyl ) ethyl ester

A mixture of ( R )-1-(3-fluorophenyl)ethyl(4-bromo-1-methyl- 1H -1,2,3-triazol-5-yl)carbamate (Intermediate 2D) (0.370 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)aniline (0.407 mmol), tetrakis(triphenylphosphine)palladium(0) (0.037 mmol) and sodium carbonate (1.11 mmol) in 1,4-dioxane/water (3:1, 3.0 mL) was degassed by hydrogen for 10 min. The vessel was sealed and heated at 100 °C for 18 h. The reaction was cooled to room temperature, diluted with saturated aqueous _NH4Cl solution, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give (R)-(4-(4-aminophenyl)-1-methyl- 1H -1,2,3-triazol-5-yl)carbamic acid 1-(3-fluorophenyl)ethyl ester (Intermediate 8C). Step 2 : (R)-(1- methyl -4-(4-(2, 2, 2- trifluoroacetamido ) phenyl )-1H-1,2,3- triazol -5- yl ) carbamic acid 1-(3- fluorophenyl ) ethyl ester ( Compound 1)

To a solution of ( R )-1-(3-fluorophenyl)ethyl(4-(4-aminophenyl)-1-methyl- 1H -1,2,3-triazol-5-yl)carbamate (Intermediate 8C) (0.082 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic anhydride (0.122 mmol). The solution was stirred at room temperature for 3 hours. The reactant was concentrated under reduced pressure and purified by reverse phase chromatography to give (R)-1-(3-fluorophenyl)ethyl(1-methyl-4-(4-(2,2,2-trifluoroacetamido)phenyl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 6). (MS ( m/z ) 452.0 [MH] ⁺ ). 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 11.36 (s, 1H), 9.97 (major) and 9.55 (minor) (s, 1H), 7.73 (s, 4H), 7.53-6.66 (m, 4H), 5.89-5.60 (m, 1H), 3.85 (s, 3H), 1.56 (major) and 1.24 (minor) (s, 3H). Example 9 : Preparation of [(1R)-1-(2- chloro -3- pyridinyl ) ethyl ] N-[5-[5-[(1- cyanocyclopropanecarbonyl ) amino ] pyrimidinyl -2- yl ]-3- methyl - triazol -4- yl ] carbamate ( Compound 2) Step 1 : [(1R)-1-(2- chloro -3- pyridinyl ) ethyl ] N-[5-(5- aminopyrimidin -2- yl )-3- methyl - triazol -4- yl ] carbamate

To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) (1.39 mmol) in tetrahydrofuran (14 mL) at -78 °C was added a 1 M solution of lithium bis(trimethylsilyl)amide (1.53 mmol) in THF. After 10 min, a 2.5 M solution of n-butyllithium (2.77 mmol) in hexanes was added. After 45 min, a 1.9 M solution of zinc chloride (4.30 mmol) in 2-MeTHF was added and the reaction was stirred at room temperature for 45 min. At this point, 2-bromopyrimidin-5-amine (1.94 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (0.139 mmol) were added to the reaction, and the reaction mixture was heated to 70 °C for 1 hour. After the reaction was complete, the mixture was cooled and quenched with saturated aqueous ammonium chloride. The mixture was diluted with ethyl acetate, and the organics were separated. The aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give [(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(5-aminopyrimidin-2-yl)-3-methyl-triazol-4-yl]carbamate. Step 2 : [(1R)-1-(2- chloro -3- pyridyl ) ethyl ]N-[5-[5-[(1- cyanocyclopropanecarbonyl ) amino ] pyrimidin -2- yl ]-3- methyl - triazol -4- yl ] carbamate ( Compound 2)

A mixture of [(1R)-1-(2-chloro-3-pyridinyl)ethyl] N-[5-(5-aminopyrimidin-2-yl)-3-methyl-triazol-4-yl]carbamate (0.08 mmol), 1-cyanocyclopropanecarboxylic acid (0.096 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.096 mmol) in pyridine (1.0 mL) was stirred at room temperature for 30 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give [(1R)-1-(2-chloro-3-pyridyl)ethyl] N-[5-[5-[(1-cyanocyclopropanecarbonyl)amino]pyrimidin-2-yl]-3-methyl-triazol-4-yl]carbamate (MS ( m/z ) 468.1 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.04 (s, 2H), 8.30 (s, 1H), 8.00 (s, 1H), 7.45 (s, 1H), 6.08 (q, J = 6.7 Hz, 1H), 3.99 (s, 3H), 1.82 - 1.75 (m, 2H), 1.73 - 1.67 (m, 2H), 1.59 (s, 3H). Example 10 : Preparation of Compounds 3 and 4

Compounds 3 and 4 were generally synthesized according to Scheme B, step 1. For example, (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(6-(3-methylureido)pyridin-3-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 3) was prepared as follows.

A mixture of 1-methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2-yl)urea (1.67 mmol), (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A) (0.556 mmol) and sodium carbonate (1.67 mmol) in 1,4-dioxane/water (7 mL) at a ratio of 3:1 was heated to 100 °C for 1 hour. The mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to obtain (R) -1-(2- chloropyridin -3- yl ) ethyl (1- methyl -4-(6-(3 -methylureido ) pyridin -3 - yl )-1H-1,2,3 - triazol -5- yl ) carbamate (Compound 3). (MS ( m/z ) 432.1 [M+H] ⁺ ). 1H NMR (400 MHz, DMSO-d6) δ 10.05 (bs, 1H), 9.41 (bs, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.40 (bs, 1H), 8.03-7.85 (m, 3H), 7.54 (bs, 1H), 7.42 (d, J = 8.7 Hz, 1H), 5.93 (m, 1H), 3.85 (s, 3H), 2.75 (d, J = 4.2 Hz, 3H), 1.60 (bs, 3H).

Compound 4 was prepared similarly according to Scheme C, step 2, by reacting 1-(2-chloropyridin-3-yl)ethyl (R)-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) (Example 3) with 1-ethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2-yl)urea following the general method described for compound 3 to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(6-(3-ethylureido)pyridin-3-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 4). (MS ( m/z ) 444.2 [M+H] ⁺ ). 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.35 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.09 - 7.81 (m, 2H), 7.69 - 7.17 (m, 5H), 6.01 (m, 1H), 3.85 (s, 3H), 3.31 - 3.09 (m, 2H), 1.57 (bs, 3H), 1.11 (t, J = 7.2 Hz, 3H). Example 11 : Preparation of [(1R)-1-(2- chloro -3- pyridinyl ) ethyl ] N-[5-(5- acetamido -6- fluoro -2- pyridinyl )-3- methyl - triazol -4- yl ] carbamate ( Compound 5) Step 1 : N-(6- bromo -2- fluoro -3- pyridyl ) acetamide

To a solution of 6-bromo-2-fluoro-pyridin-3-amine (5.24 mmol) in dichloromethane (17 mL) was added pyridine (26.2 mmol) followed by acetyl chloride (22.9 mmol). The reaction was stirred overnight. After completion of the reaction, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give N-(6-bromo-2-fluoro-3-pyridinyl)acetamide. Step 2 : 5-(5- Acetamido -6- fluoro -2- pyridinyl )-3 -methyl - triazole -4- carboxylic acid

A mixture of N-(6-bromo-2-fluoro-3-pyridyl)acetamide (0.485 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (0.0485 mmol), bis(pinacolato)diboron (0.728 mmol) and potassium acetate (0.728 mmol) in 1,4-dioxane (5 mL) was heated to 100 °C for 1 hour. At this time, the reaction was cooled to room temperature and 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1) (0.485 mmol), potassium carbonate (0.971 mmol) and water (1.5 mL) were added to the reaction. The reaction was purged with nitrogen and heated to 100 °C for 1 hour. After completion of the reaction, the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give 5-(5-acetamido-6-fluoro-2-pyridinyl)-3-methyl-triazole-4-carboxylic acid. Step 3 : [(1R)-1-(2- chloro -3- pyridinyl ) ethyl ] N-[5-(5- acetamido -6- fluoro -2- pyridinyl )-3- methyl - triazol -4- yl ] carbamate ( Compound 5)

To a mixture of 5-(5-acetamido-6-fluoro-2-pyridinyl)-3-methyl-triazole-4-carboxylic acid (0.372 mmol), 1-propanephosphonic acid cyclic anhydride (50% in DMF, 0.559 mmol) and azidotrimethylsilane (0.559 mmol) acid in THF (1.9 mL) was added triethylamine (0.745 mmol) dropwise. (1R)-1-(2-chloro-3-pyridinyl)ethanol (0.559 mmol) was added and the flask was heated at 70 °C for 1 hour. After the reaction was complete, the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give [(1R)-1-(2-chloro-3-pyridinyl)ethyl] N-[5-(5-acetamido-6-fluoro-2-pyridinyl)-3-methyl-triazol-4-yl]carbamate (Compound 5). (MS ( m/z ) 434.1 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.54 (dd, J = 9.8, 8.3 Hz, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.45 (s, 1H), 6.09 (q, J = 6.4 Hz, 1H), 3.96 (s, 3H), 2.21 (s, 3H), 1.57 (d, J = 48.3 Hz, 3H). Example 12 : Preparation of 1-(2- chloropyridin -3- yl ) ethyl (R)-(4-(4- aminophenyl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 8B) Step 1 : 4-(4-(( tert-butyloxycarbonyl ) amino ) phenyl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid

To a mixture of (4-((tert-butyloxycarbonyl)amino)phenyl)boronic acid (2.7 mmol) and 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1) (2.4 mmol) were added potassium carbonate (7.3 mmol) and Pd(PPh ₃ ) ₄ (0.24 mmol). The mixture was suspended in 20 mL of a 10:1 mixture of dioxane/water and bubbled with hydrogen for 5 min. The reaction was sealed and heated to 100° C. for 16 hours. The reaction was diluted with 1 M aqueous HCl and brine, and extracted with ethyl acetate (25 mL×2). The combined organics were dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 4-(4-((tert-butyloxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid. Step 2 : (R)-1-(2- chloropyridin -3- yl ) ethyl (4-(4-(( tert-butyloxycarbonyl ) amino ) phenyl ) -1- methyl -1H-1,2,3- triazole - 5- yl ) carbamate

4-(4-((tributyloxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (1 mmol), 50% 1-propanephosphonic anhydride solution (1.4 mmol) were in DMF, and trimethylsilylazide (1.4 mmol) was suspended in THF (3 mL). Triethylamine (1.4 mmol) was added and the resulting solution was stirred at room temperature for 30 min. (1R)-1-(2-chloro-3-pyridinyl)ethanol (1.4 mmol) was added and the mixture was heated at reflux for 12 h. The reaction mixture was cooled to room temperature and the THF was removed in vacuo. The crude material was purified by silica gel column chromatography to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(4-((tributyloxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. Step 3 : 1-( 2- chloropyridin -3- yl ) ethyl (R)-(4-(4- aminophenyl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 8B)

4 M HCl in 1,4-dioxane (1 mL) was added to 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(4-((tributyloxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.5 mmol). The resulting suspension was stirred at room temperature for 18 h. The reaction was concentrated to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a hydrochloride salt (Intermediate 8B). Example 13 : Preparation of (R)-(4-(4- acetamidophenyl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 6) Step 4 : (R) -1-(2- chloropyridin -3- yl ) ethyl (4-(4- acetamidophenyl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Compound 6)

(R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 8B) hydrochloride (0.08 mmol) was dissolved in dichloromethane (1 mL), pyridine (0.2 mL). Acetyl chloride (0.16 mmol) was added dropwise at room temperature. After 30 min, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 0.5 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 min. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-acetamidophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 6). (MS ( m/z ) 415.08 [M+H] ⁺ ). ^1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 8.06 (s, 1H), 7.65 (s, 4H), 7.56 - 6.99 (m, 1H), 6.11 (s, 1H), 3.95 (s, 3H), 2.17 (s, 3H), 1.82 - 1.19 (m, 3H). Example 14 : Preparation of (R)-(4-(4-(( methoxycarbonyl ) amino ) phenyl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 7)

(R)-1-(2-chloropyridin-3-yl)ethyl(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 8B) hydrochloride (0.08 mmol) was dissolved in dichloromethane (1 mL), pyridine (0.2 mL). Methyl chloroformate chloride (0.16 mmol) was added dropwise at room temperature. After 30 minutes, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 0.5 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl (4-(4-methoxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 7). (MS ( m/z ) 431.1 [M+H] ⁺ ). ^1H NMR (400 MHz, Methanol-d4) δ 8.60 - 8.13 (m, 1H), 8.06 (s, 1H), 7.77 - 7.10 (m, 5H), 6.23 - 5.90 (m, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 1.80 - 1.38 (m, 3H). Example 15 : Preparation of (S)-2- fluoro -1- phenylethyl (4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 8D) Step 1 : (S)-(6-(5-(((2- fluoro -1- phenylethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyridin -3- yl ) carbamic acid tributyl ester

Following the procedure described in Example 12 for the preparation of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(4-((t-butyloxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, using (S)-2-fluoro-1-(3-fluorophenyl)ethan-1-ol (0.73 mmol) instead of (R)-1-(2-chloropyridin-3-yl)ethan-1-ol, (S)-(6-(5-(((2-fluoro-1-phenylethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate was obtained. Step 2 : (S)-2- Fluoro -1- phenylethyl (4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 8D)

4 M HCl in 1,4-dioxane (1 mL) was added to tributyl (S)-(6-(5-(((2-fluoro-1-phenylethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate (0.34 mmol). The resulting suspension was stirred at room temperature for 3 h. The reaction was concentrated to give 2-fluoro-1-phenylethyl (S)-(4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a hydrochloride salt (Intermediate 8D). Example 16 : Preparation of (R)-(4-(5-(1- cyanocyclopropane -1 -carboxamido ) pyrrolidone -2- yl ) -1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 8) Step 1 : (R)-(4-(5-(( tributyloxycarbonyl ) amino ) pyrrolidone -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester

To a solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) (0.42 mmol) in 3 mL THF was added 1 N lithium bis(trimethylsilyl)amide in THF (0.50 mmol, 1 M) dropwise at -78 °C. After 15 min, a solution of 1.6 M n-butyllithium (nBuLi) in hexanes (0.83 mmol) was added dropwise. After 15 min, a solution of 1.9 M zinc chloride (ZnCl ₂ ) in THF (1.0 mmol) was added dropwise, and the reaction was allowed to warm to room temperature over 20 min. A solution of tributyl (5-bromopyridinium-2-yl)carbamate (bromopyridinium) (0.50 mmol) and tributyl (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3) (0.042 mmol) in THF was added and the reaction was heated to 70 °C for 2 hours. The reaction was then cooled to room temperature and quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. Purification by silica gel chromatography (0-20% DCM/MeOH) gave (R)-(4-(5-((tributyloxycarbonyl)amino)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2- chloropyridin -3-yl)ethyl ester. Step 2 : (R)-(4-(5- aminopyrrolidone -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester

A solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((tributyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.126 mmol) in 4N HCl in dioxane was stirred at room temperature for 1 hour. The reaction was concentrated and placed under vacuum overnight to give 1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. Step 3 : (R)-(4-(5-(1- cyanocyclopropane -1- carboxamido ) pyrrolidone -2- yl )-1- methyl - 1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3 - yl ) ethyl ester ( Compound 8)

A solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.0729 mmol) in 0.2 mL DMF was treated with pyridine (0.729 mmol), 1-cyanocyclopropane-1-carboxylic acid (0.114 mmol) and EDC (0.0875 mmol) and stirred at room temperature for 3 h. Dilution with aqueous MeCN and purification by RP HPLC gave 1-(2-chloropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 27). (MS ( m/z ) 467.9 [M+H] +). 1H NMR (400 MHz, methanol-d4) d 9.01 (s, 1H), 8.84 (s, 1H), 8.51-7.91 (m, 2H), 7.46 (s, 1H), 6.30 - 5.74 (m, 1H), 3.97 (s, 3H), 1.84 - 1.38 (m, 7H). Example 17 : Preparation of (R)-(4-(5- acetamido -3- fluoropyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 9) Step 1 : N-(6- bromo -5- fluoro -3- pyridyl ) acetamide

To a solution of 6-bromo-5-fluoro-pyridin-3-amine (5.24 mmol) in dichloromethane (17 mL) was added pyridine (26.2 mmol) followed by acetyl chloride (22.9 mmol). The reaction was stirred overnight. After completion of the reaction, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 6-bromo-5-fluoro-pyridin-3-amine. Step 2 : 4-(5- Acetylamino -3- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid

To a mixture of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1) (1.3 mmol) in tetrahydrofuran (20 mL) at -78 °C was added a 1 M solution of lithium bis(trimethylsilyl)amide (1.3 mmol) in THF. After 10 minutes, a 2.5 M solution of n-butyllithium (2.5 mmol) in hexanes was added. After 45 minutes, a 1.9 M solution of zinc chloride (2.5 mmol) in 2-MeTHF was added, and the reaction was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was bubbled with argon for 5 minutes, and N-(6-bromo-5-fluoro-3-pyridyl)acetamide (0.84 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (0.08 mmol) were subsequently added. The reaction was heated at 70 °C for 2 hours, after which the reaction was cooled and diluted with 1 M aqueous hydrogen chloride solution (20 mL). The reaction mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to give 4-(5-acetamido-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid, which was used in the next step without further purification. Step 3 : (R) -1-(2- chloropyridin -3- yl ) ethyl (4-(5- acetamido -3- fluoropyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Compound 9)

(R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-acetamido-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.14 mmol), 50% 1-propanephosphonic anhydride solution (0.29 mmol), and trimethylsilylazide (0.29 mmol) in DMF were suspended in THF (2 mL). Triethylamine (0.43 mmol) was added and the resulting solution was stirred at room temperature for 30 minutes. (1R)-1-(2-chloro-3-pyridinyl)ethanol (0.29 mmol) was added and the mixture was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature and the THF was removed in vacuo. The crude material was purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-acetamido-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 29). (MS ( m/z ) 434.0 [M+H] ⁺ ). ^1H NMR (400 MHz, Methanol- _d4 ) δ 8.52 (s, 1H), 8.33 (s, 1H), 8.19 - 7.76 (m, 2H), 7.48 (s, 1H), 6.20 - 5.90 (m, 1H), 4.01 (s, 3H), 2.21 (s, 3H), 1.60 (s, 3H). Example 18 : Preparation of (R)-(4-(5- amino -4- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Intermediate 7B) Step 1 : (R)-(4-(5-(( tributyloxycarbonyl ) amino )-4- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3 - yl ) ethyl ester

To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A) (1 mmol) in tetrahydrofuran (15 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide (1.2 mmol) in tetrahydrofuran at −78° C. After 10 minutes, a 2.5 M solution of n-butyllithium (2.5 mmol) in hexanes was added. After 45 minutes, a 1.9 M solution of zinc chloride (2.5 mmol) in 2-methyltetrahydrofuran was added, and the reaction was allowed to warm to room temperature and stirred at room temperature for 30 minutes. The reaction mixture was bubbled with hydrogen for 5 minutes, and then tributyl (6-chloro-4-fluoropyridin-3-yl)carbamate (1.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (0.1 mmol) were added. The reaction mixture was heated to 70 °C for 1 hour. After the reaction was complete, the mixture was cooled and quenched with 1N aqueous hydrochloric acid (20 mL). The aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R)-(4-(5-((tributyloxycarbonyl)amino)-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3- yl )ethyl ester which was used in the next step without further purification. Step 2 : (R)-(4-(5- amino -4- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2 - chloropyridin -3- yl ) ethyl ester ( Intermediate 7B)

4 M HCl in 1,4-dioxane (1 mL) was added to 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((tributyloxycarbonyl)amino)-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.49 mmol). The resulting suspension was stirred at room temperature for 4 hours. The reaction was concentrated to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-amino-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a hydrochloride salt (Intermediate 7B). Example 19 : Preparation of (R)-(4-(5- acetamido -4- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 10)

The hydrochloride salt of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 7B) (0.05 mmol) was dissolved in dichloromethane (1 mL) and pyridine (0.2 mL). Acetyl chloride (0.1 mmol) was added dropwise at room temperature. After 30 minutes, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 1 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-(4-(5-acetamido-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester. (Compound 30) (MS ( m/z ) 434.0 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.17 (d, J = 9.8 Hz, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.09 (s, 1H), 7.79 (d, J = 11.5 Hz, 1H), 7.48 (s, 1H), 6.18 - 6.00 (m, 1H), 3.99 (s, 3H), 2.24 (s, 3H), 1.62 (s, 3H). Example 20 : Preparation of 1-( 2- chloropyridin -3- yl ) ethyl (R)-(4-(5-(( tributyloxycarbonyl ) amino ) pyridin -2- yl )-1- methyl - 1H-1,2,3- triazol -5- yl ) carbamate ( Compound 11)

To a mixture of 4-(5-((tributyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (9.4 mmol), 1-propanephosphonic acid cyclic anhydride (50% in THF, 14.1 mmol) and azidotrimethylsilane (14.1 mmol) acid in THF (100 mL) was added triethylamine (23.5 mmol) dropwise. The reaction mixture was heated at 70 °C for 1 hour, followed by the addition of (R)-1-(2-chloropyridin-3-yl)ethan-1-ol (18.8 mmol) at the same temperature. After heating for 24 hours, the reaction was cooled to room temperature, concentrated and purified by silica gel chromatography to provide (R)-(4-(5-((tributyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester. (Compound 11) (MS ( m/z ) 474.12 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d4) δ 8.67 (s, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 7.94 (dd, J = 8.7, 2.6 Hz, 1H), 7.84 (dd, J = 8.6, 0.8 Hz, 1H), 7.47 (s, 1H), 6.07 (d, J = 6.7 Hz, 1H), 3.98 (s, 3H), 1.75 - 1.46 (m, 12H). Example 21 : Preparation of 1-(2- chloropyridin -3- yl ) ethyl (R)-(4-(5- aminopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 5A)

4 M HCl in 1,4-dioxane (20 mL) was added to 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((tributyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (6.9 mmol). The resulting suspension was stirred at room temperature for 18 h. The reaction was concentrated to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a hydrochloride salt (Intermediate 5A). Example 22 : Preparation of (R)-(4-(5- aminopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Intermediate 5B) Step 1 : (R)-(6-(5-(((1-(2,5 -difluoropyridin -3 -yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyridin -3- yl ) carbamic acid tributyl ester

To a mixture of 4-(5-((tri-butyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (10.6 mmol), 1-propanephosphonic acid cyclic anhydride (50% in THF, 16 mmol) and azidotrimethylsilane (16 mmol) in THF (15 mL) was added triethylamine (27 mmol) dropwise. The reaction mixture was heated at 70 °C for 0.5 h, followed by the addition of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol (21 mmol) at the same temperature. After heating for 24 hours, the reaction was cooled to room temperature, concentrated and purified by silica gel chromatography to give (R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamic acid tert-butyl ester. Step 2 : (R)-(4-(5- aminopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Intermediate 5B)

4 M HCl in 1,4-dioxane (15 mL) was added to tributyl (R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate (4.2 mmol). The resulting suspension was stirred at room temperature for 18 hours. The reaction was concentrated to give 1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as the hydrochloride salt (Intermediate 5B). Example 23 : Preparation of (R) -1-(2- chloro -5- fluoropyridin -3- yl ) ethyl (4-(5- aminopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 5C)

Following the procedure described in Example 22 for the preparation of 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B), using (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethan-1-ol (1.7 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5C) was obtained. Example 24 : Preparation of (R)-(4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- fluoropyridin -3- yl ) ethyl ester ( Intermediate 5D)

Following the preparation of 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) as described in Example 22, using (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (7.0 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, (R)-1-(2-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5D) was obtained. Example 25 : Preparation of (R)-(4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(5- fluoro -2- methylpyridin -3- yl ) ethyl ester ( Intermediate 5E)

The preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) was followed as described in Example 22, using (R)-1-(5-fluoro-2-methylpyridin-3-yl)ethan-1-ol (6.4 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol to give (R)-1-(5-fluoro-2-methylpyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5E). Example 26 : Preparation of (R)-(4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chlorophenyl ) ethyl ester ( Intermediate 6A)

Following the preparation of 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) as described in Example 22, using (R)-1-(2-chlorophenyl)ethan-1-ol (3.2 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, (R)-1-(2-chlorophenyl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6A) was obtained. Example 27 : Preparation of (S) -2- Fluoro - 1- (3- fluorophenyl ) ethyl (4-(5- aminopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Intermediate 6B)

Following the description of Example 22 for the preparation of 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B), (S)-2-fluoro-1-(3-fluorophenyl)ethan-1-ol (2.3 mmol) was used instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol to give 2-fluoro-1-(3-fluorophenyl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6B). Example 28 : Preparation of 1-(2- chloro -6- fluoropyridin - 3 -yl ) ethan -1- ol

2-Chloro-6-fluoronicotinaldehyde (2.51 mmol) dissolved in methyltetrahydrofuran (20 ml) was cooled in an ice/acetonitrile bath and then methylmagnesium bromide solution (3.0 M, 7.20 mmol) was added dropwise. The reaction mixture was quenched by adding ethanol and then diluted with ethyl acetate and washed with 10% citric acid. The organic layer was concentrated. The residue was purified by column chromatography to give 1-(2-chloro-6-fluoropyridin-3-yl)ethan-1-ol. Example 29 : Preparation of 1-(2- fluoro -5- methylpyridin -4- yl ) ethan -1- ol:

A solution of 2-fluoro-4-iodo-5-methylpyridine (4.22 mmol) in 20 mL THF was cooled to 0 °C and treated with 1.6 M nBuLi in hexanes (5.06 mmol). DMF (12.7 mmol) was added dropwise after 15 min. The reaction was stirred for 30 min, then warmed to room temperature and quenched with saturated NH ₄ Cl. The mixture was extracted with EtOAc, dried over MgSO ₄ and concentrated to give 2-fluoro-5-methylisonicotinate aldehyde. 2-Fluoro-5-methylisonicotinate aldehyde (5.5 mmol) was dissolved in 25 mL THF and cooled to -15 °C in an acetone ice bath. Treated with 3 M MeMgBr in THF (11.2 mmol) and stirred for 20 min. Quenched with saturated NH ₄ Cl and extracted with EtOAc, dried over MgSO ₄ , filtered and concentrated to give 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol (MS (m/z) 155.9 [M+H]+). Example 30 : Preparation of 1-(2,5 -difluoropyridin -4- yl ) ethan -1- ol

Following the procedure described in Example 29 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, 2,5-difluoroisonicotinaldehyde (11.9 mmol) was used instead of 2-fluoro-5-methylisonicotinaldehyde to give 1-(2,5-difluoropyridin-4-yl)ethan-1-ol. (MS (m/z) 160.11 [M+H]+). Example 31 : Preparation of 1-(5- bromo -2- fluoropyridin -3- yl ) ethan -1- ol

Following the procedure described in Example 29 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, 5-bromo-2-fluoronicotinate (7.35 mmol) was used instead of 2-fluoro-5-methylisonicotinate to give 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol. (MS (m/z) 220.01 [M+H]+). Example 32 : Preparation of 1-(5- bromo -2- chloropyridin -3- yl ) ethan -1- ol

Following the procedure described in Example 29 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, 5-bromo-2-chloronicotinaldehyde (10.6 mmol) was used instead of 2-fluoro-5-methylisonicotinaldehyde to give 1-(5-bromo-2-chloropyridin-3-yl)ethan-1-ol. (MS (m/z) 235.99 [M+H]+). Example 33 : Preparation of 1-(2,5 -difluoropyridin -4- yl ) ethan -1- ol

Following the procedure described in Example 29 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, 5-bromo-2-fluoronicotinate (7.4 mmol) was used instead of 2-fluoro-5-methylisonicotinate to give 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol. (MS (m/z) 220.01 [M+H]+). Example 34 : Preparation of 1-(2- chloro -6- fluoropyridin -3- yl ) ethyl (4-(5- aminopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol - 5- yl ) carbamate ( Intermediate 5F)

Following the preparation of 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) as described in Example 22, using 1-(2-chloro-6-fluoropyridin-3-yl)ethan-1-ol (0.34 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol, 1-(2-chloro-6-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5F) was obtained. Example 35 : Preparation of 1-(5- bromo -2- fluoropyridin - 3- yl ) ethyl (1 - methyl -4-(5-(2,2,2 -trifluoroacetamido ) pyridin -2- yl )-1H-1,2,3- triazol -5- yl ) carbamate ( Compound 12) Step 1 : (6-(5-(((1-(5- bromo -2- fluoropyridin -3- yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyridin -3- yl ) carbamic acid tributyl ester

A solution of tributyl (6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate (0.125 mmol) in 0.2 ML THF was treated with T3P (0.25 mmol), trimethylsilyl azide (TMS-N3) (0.25 mmol) and triethylamine (TEA) (0.25 mmol) and stirred at room temperature for 20 minutes. A solution of 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol in 200 μL THF was added and the mixture was heated at 65° C. for 90 minutes. The mixture was then diluted with DCM and washed with aqueous NaHCO3 solution and purified by silica gel chromatography to give (6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamic acid tert-butyl ester. Step 2 : 2,2,2- Trifluoroacetic acid, 6-(5-(((1-(5- bromo -2 - fluoropyridin -3- yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyridin -3- ammonium salt

Tributyl (6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate (0.125 mmol) was dissolved in 2 mL DCM and 2 mL trifluoroacetic acid (TFA). Stirred for 5 minutes then concentrated. Dissolved in 15 mL dichloroethane and concentrated again. This was repeated 2 times and the resulting oil was left under high vacuum overnight. The obtained 2,2,2-trifluoroacetic acid and 6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl ) pyridine-3-ammonium salt were used in the next step in crude form. Step 3 : 1-( 5-bromo-2- fluoropyridin -3- yl ) ethyl ( 1 - methyl -4-(5-(2,2,2- trifluoroacetamido ) pyridin - 2- yl ) -1H -1,2,3 - triazol - 5- yl ) carbamate ( Compound 12)

2,2,2-Trifluoroacetic acid, 6-(5-(((1-(5-bromo-2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-ammonium salt (0.125 mmol) were dissolved in 2 mL DCM and cooled to 0 °C. This solution was treated with pyridine (0.36 mmol) and methanesulfonic anhydride (0.156 mmol). Allowed to warm to room temperature and stirred for 30 min. The reaction was concentrated and the residue was dissolved in MeCN and water. Purification by RP HPLC gave 1-(5-bromo-2-fluoropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 12) (MS (m/z) 532.04 [M+H]+). 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.85 (m, 1H), 8.37 - 8.32 (m, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 2.7 Hz, 1H), 5.80 (s, 1H), 3.89 (s, 3H), 3.08 (s, 3H), 1.77 - 1.38 (m, 3H). Example 36 : Preparation of 1-(5- bromo -2- chloropyridin -3- yl ) ethyl (1- methyl -4-(5-(2,2,2- trifluoroacetamido ) pyridin -2- yl )-1H-1,2,3- triazol -5- yl ) carbamate ( Compound 13)

Following the synthesis of 1-(5-bromo-2-fluoropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate described in Example 35, 1-(5-bromo-2-chloropyridin-3-yl)ethan-1-ol (0.143 mmol) was used instead of 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol to give 1-(5-bromo-2-chloropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 13). (MS (m/z) 548.03 [M+H]+). 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.94 (s, 1H), 8.81 (s, 1H), 8.54 (s, 1H), 8.12 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.38 (s, 1H), 5.84 (s, 1H), 3.91 (s, 3H), 1.58 (s, 3H). Example 37 : Preparation of 1-( 5- chloro -2 - fluoropyridin -3- yl ) ethyl (R)-(4-(5- acetamidopyridin - 2- yl )-1 - methyl - 1H -1,2,3- triazol -5- yl ) carbamate ( Compound 14) Step 1 : (R)-(4-(5-(( tributyloxycarbonyl ) amino ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(5- chloro -2- fluoropyridin -3- yl ) ethyl ester

Following the procedure described in Example 35, step 1 for the synthesis of 1-(5-bromo-2-fluoropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-)-1H-1,2,3-triazol-5-yl)carbamate, using (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethan-1-ol (0.43 mmol) instead of 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol, (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl (4-(5-((tri-butyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was obtained. (MS (m/z) 492.03 [M+H]+). Step 2 : (R)-(4-(5- aminopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(5- chloro -2- fluoropyridin -3- yl ) ethyl ester hydrochloride

A solution of (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-((tri-butyloxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.193 mmol) in 4N HCl in dioxane was stirred at room temperature for 1 hour. The reaction was concentrated and placed under vacuum overnight to give (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride as an oil. Step 3 : (R) -1-(5- chloro -2- fluoropyridin -3 - yl ) ethyl (4-(5- acetamidopyridin -2- yl )-1 - methyl -1H-1,2,3- triazol -5- yl ) carbamate ( Compound 14)

A solution of (R)-1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (0.193 mmol) in 0.5 mL DCM was treated with pyridine (2.9 mmol) and cooled to 0 °C. Acetyl chloride (0.212 mmol) was added and the mixture was stirred at 0 °C for 45 min. The reaction was concentrated in vacuo and purified by RP HPLC to give 1-(5-chloro-2-fluoropyridin-3-yl)ethyl(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 14) (MS (m/z) 434.0 [M+H]+). H NMR (400 MHz, acetonitrile-d3) δ 8.98 - 8.93 (m, 1H), 8.76 (s, 1H), 8.27 (d, J = 3.0 Hz, 1H), 8.24 - 8.14 (m, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.81 (ddd, J = 9.0, 3.1, 0.7 Hz, 1H), 3.97 (s, 3H), 2.16 (s, 3H), 1.62 - 1.55 (m, 3H). Example 38 : Preparation of (R)-(4-(5- acetamidopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin -3- yl ) ethyl ester ( Compound 15)

The synthesis of 1-(5-chloro-2-fluoropyridin-3-yl)ethyl (R)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using 1-(2-chloro-5-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.23 mmol), instead of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(5-chloro-2-fluoropyridin-3-yl)ethyl ester, to obtain (R)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester (Compound 15). (MS (m/z) 434.0 [M+H]+) H NMR (400 MHz, acetonitrile-d3) δ 8.98 - 8.93 (m, 1H), 8.76 (s, 1H), 8.27 (d, J = 3.0 Hz, 1H), 8.24 - 8.14 (m, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.81 (ddd, J = 9.0, 3.1, 0.7 Hz, 1H), 3.97 (s, 3H), 2.16 (s, 3H), 1.62 - 1.55 (m, 3H). Example 39 : Preparation of (R)-(4-(5- carboxamidopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 16)

To acetic anhydride (3 mmol) was added formic acid (5 mmol) under an atmosphere of argon at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. Then (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5A) (0.37 mmol) in THF (0.33 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was concentrated to dryness and then co-evaporated with toluene. The residue was purified by reverse phase HPLC to give (R)-(4-(5-carboxamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester (Compound 41) (MS ( m/z ) 402.0 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.89 (d, 1H), 8.37 (d, 2H), 8.19 - 8.03 (m, 1H), 8.02 - 7.89 (m, 1H), 7.80 - 7.59 (m, 1H), 7.49 (s, 1H), 6.09 (m, 1H), 4.00 (d, 3H), 1.63 (s, 3H). Example 40 : Preparation of 1-(2-chloropyridin-3-yl)ethyl (R)-( 4- (5-(( methoxycarbonyl ) amino ) pyridin -2- yl )-1- methyl - 1H-1,2,3 - triazol - 5 - yl ) carbamate ( Compound 17 )

(R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5A) (0.78 mmol) was dissolved in dichloromethane (1 mL), pyridine (0.2 mL). Methyl chloroformate chloride (0.14 mmol) was added dropwise at room temperature. After 30 minutes, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 0.5 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester. (Compound 17) (MS ( m/z ) 432.1 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.70 (s, 1H), 8.31 (s, 1H), 8.13 - 7.92 (m, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 6.21 - 5.92 (m, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 1.61 (s, 3H). Example 41 : Preparation of 2-fluoro -1- phenylethyl (S)-(4-(4-(( methoxycarbonyl ) amino ) phenyl )-1- methyl - 1H-1,2,3 - triazol -5 - yl ) carbamate ( Compound 18 )

The synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using 2-fluoro-1-phenylethyl (4-(4-aminophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 8D) (0.06 mmol) was used to replace (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate with 1-(2-chloropyridin-3-yl)ethyl ester to give (S)-(4-(4-((methoxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 18) (MS ( m/z ) 414.1 [M+H] ⁺ ). ^1H NMR (400 MHz, Methanol- _d4 ) δ 7.87 - 6.82 (m, 9H), 6.03 (s, 1H), 4.81 - 4.56 (m, 2H), 3.92 (s, 3H), 3.78 (s, 3H). Example 42 : Preparation of (S)-(4-(5-(( methoxycarbonyl ) amino ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 2- fluoro -1-(3- fluorophenyl ) ethyl ester ( Compound 19)

The synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using 2-fluoro-1-(3-fluorophenyl)ethyl (S)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6B) (0.05 mmol) was used to replace (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate to obtain (S)-2-fluoro-1-(3-fluorophenyl)ethyl (4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (Compound 19) (MS ( m/z ) 433.2 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.69 (s, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.57 - 6.62 (m, 4H), 6.09 - 5.77 (m, 1H), 4.80 - 4.47 (m, 2H), 3.97 (s, 3H), 3.79 (s, 3H). Example 43 : Preparation of (R)-(4-(5-(( methoxycarbonyl ) amino ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chlorophenyl ) ethyl ester ( Compound 20)

The synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using 1-(2-chlorophenyl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6A) (0.03 mmol) was used to replace (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate with 1-(2-chloropyridin-3-yl)ethyl to give (R)-(4-(5-((methoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate with 1-(2-chlorophenyl)ethyl (Compound 20). (MS ( m/z ) 431.2 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.74 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.74 - 7.00 (m, 4H), 6.14 (d, J = 6.7 Hz, 1H), 3.96 (s, 3H), 3.79 (s, 3H), 1.42 (s, 3H). Example 44 : Preparation of 1-(2-chloropyridin-3-yl) ethyl (R)-(4-(5-(( ethoxycarbonyl ) amino ) pyridin -2- yl )-1- methyl - 1H -1,2,3- triazol - 5 - yl ) carbamate ( Compound 21 )

(R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5A) (0.10 mmol) suspended in dichloromethane (1 mL) was treated with N,N-diisopropylethylamine (30 µL, 0.17 mmol) followed by ethyl chloroformate (0.210 mmol). The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated. The residue was purified on HPLC and the elution fraction was dried by lyophilization. The lyophilized solid was dissolved in methyltetrahydrofuran (1 mL) and treated with 1 N sodium hydroxide solution (400 µL). The reaction mixture was heated at 55 °C for 30 minutes. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified on HPLC to provide (R)-(4-(5-((ethoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester (Compound 21). (MS ( m/z ) 446.0 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.80 (s, 1H), 8.34 (s, 1H), 8.06 (d, J = 8.7 Hz, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 6.08 (d, J = 6.9 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 1.65 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). Example 45 : Preparation of (R)-(4-(5-(( isobutoxycarbonyl ) amino ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 22)

Following the procedure described in Example 44 for the synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((ethoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, isobutyl chloroformate (0.2 mmol) was used instead of methyl chloroformate to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((isobutoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 22). (MS ( m/z ) 474.1 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.84 (s, 1H), 8.34 (s, 1H), 8.09 (d, J = 8.9 Hz, 2H), 7.90 (d, J = 8.6 Hz, 1H), 7.51 (s, 1H), 6.09 (d, J = 7.1 Hz, 1H), 4.01 (d, J = 6.7 Hz, 2H), 4.00 (s, 4H), 2.04 (dq, J = 13.4, 6.7 Hz, 1H), 1.65 (s, 3H), 1.03 (d, J = 6.7 Hz, 6H). Example 46 : Preparation of (R)-(4-(5- acetamidopyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 23)

The hydrochloride salt of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5A) (0.07 mmol) was dissolved in dichloromethane (1 mL) and pyridine (0.2 mL). Acetyl chloride (0.14 mmol) was added dropwise at room temperature. After 30 min, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 1 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 min. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (R)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester. (Compound 23) (MS ( m/z ) 416.1 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.83 (s, 1H), 8.31 (s, 1H), 8.21 - 7.95 (m, 2H), 7.89 (d, J = 8.6 Hz, 1H), 7.46 (s, 1H), 6.08 (m, 1H), 3.98 (s, 3H), 2.20 (s, 3H), 1.61 (s, 3H). Example 47 : Preparation of (R)-(4-(5- acetamidopyridin -2- yl )-1- methyl -1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2- chlorophenyl ) ethyl ester ( Compound 24)

The synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using 1-(2-chlorophenyl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6A) (0.03 mmol) was used to replace (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester to obtain (R)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chlorophenyl)ethyl ester (Compound 24). (MS ( m/z ) 415.2 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.88 (s, 1H), 8.10 (dd, J = 8.6, 2.6 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.71 - 7.05 (m, 4H), 6.29 - 5.90 (m, 1H), 3.96 (s, 3H), 2.18 (s, 3H), 1.55 (s, 3H). Example 48 : Preparation of 2- fluoro - 1- (3- fluorophenyl ) ethyl (S)-(4-(5- acetamidopyridin -2 - yl )-1- methyl -1H-1,2,3 - triazol -5- yl ) carbamate ( Compound 25 )

The synthesis of 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed using 2-fluoro-1-(3-fluorophenyl)ethyl (S)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6B) (0.05 mmol) was used to replace (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester to obtain (S)-(4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)carbamic acid 2-fluoro-1-(3-fluorophenyl)ethyl ester. (Compound 25) (MS ( m/z ) 417.2 [M+H] ⁺ ). 1H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.12 (dd, J = 8.8, 2.4 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.56 - 6.58 (m, 4H), 6.11 - 5.70 (m, 1H), 4.79 - 4.30 (m, 2H), 3.98 (s, 3H), 2.18 (s, 3H). Example 49 : Preparation of 1-( 2-fluoro- 5- methylpyridin -4 -yl ) ethyl (4-(5-(3,3- difluorocyclobutane - 1- carboxamido ) pyridin -2- yl )-1- methyl - 1H -1,2,3 - triazol - 5- yl ) carbamate ( Compound 26 ) Step 1 : 4-(5-(3,3 -difluorocyclobutane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid methyl ester

To a mixture of methyl 4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate hydrochloride (Intermediate 3A) (4.3 mmol) in a 5:1 mixture of DCM:pyridine (25 mL) was added 3,3-difluorocyclobutane-1-carboxylic acid (5.1 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.1 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 hours, at which time the reaction was concentrated to give crude methyl 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate which was used directly in the next step. Step 2 : 4-(5-(3,3 -difluorocyclobutane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid

Crude 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid methyl ester (4.3 mmol) was treated with 2 M aqueous NaOH (50 mL) and THF (25 mL) and stirred vigorously for 30 min. Next, the reaction was treated with concentrated HCl until pH = 5. The precipitate was filtered and dried under vacuum to give 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid which was used in the next step without further purification. Step 3 : 1- ( 2-fluoro-5-methylpyridin - 4 - yl ) ethyl (4-(5-(3,3- difluorocyclobutane -1 -carboxamido ) pyridin -2- yl ) -1- methyl -1H-1,2,3 - triazol -5- yl ) carbamate ( Compound 26 )

A solution of 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (0.0889 mmol) in 100 μL DMF was treated with 50% T3P in DMF (0.178 mmol) TMS-N3 (0.156 mmol) and TEA (0.267 mmol) and the mixture was stirred for 20 min. 1-(2-Fluoro-5-methylpyridin-4-yl)ethan-1-ol (0.156 mmol) was added and the reaction was heated at 65 °C for 2 h. The reaction was cooled to room temperature and purified by RP HPLC to give 1-(2-fluoro-5-methylpyridin-4-yl)ethyl (4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 26). (MS (m/z) 490.04) [M+H]+) 1H NMR (400 MHz, ACN-d3) δ 9.00 - 8.89 (m, 1H), 8.88 - 8.75 (m, 1H), 8.55 (s, 1H), 8.20 (ddt, J = 9.1, 5.8, 2.8 Hz, 1H), 8.07 - 7.97 (m, 2H), 7.06 (s, 1H), 5.90 (q, J = 6.7 Hz, 1H), 3.96 (s, 3H), 3.18 - 3.06 (m, 1H), 3.02 - 2.79 (m, 3H), 2.31 (s, 3H), 2.10 (m, 1H), 1.53 (d, J = 6.7 Hz, 3H). Example 50 : Preparation of 1-(2 - fluoro -5 -methylpyridin -4 - yl ) ethyl (4-(5-(1- cyanocyclopropane -1-carboxamido) pyridin -2- yl )-1 - methyl -1H-1,2,3 - triazol - 5 - yl ) carbamate ( Compound 27 ) Step 1 : 4-(5-(1 -cyanocyclopropane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid methyl ester

Following the procedure described in Example 49, Step 1 for the synthesis of methyl 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate, 1-cyanocyclopropane-1-carboxylic acid (5.1 mmol) was used instead of 3,3-difluorocyclobutane-1-carboxylic acid to give methyl 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate. Step 2 : 4-(5-(1- cyanocyclopropane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3 - triazole -5- carboxylic acid

Following the procedure described in Example 49, Step 2 for the synthesis of 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid, methyl 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylate (5.1 mmol) was used to replace 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid methyl ester to obtain 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2- yl )-1-methyl-1H-1,2,3-triazole-5-carboxylic acid. Step 3 : 1-(2- fluoro -5- methylpyridin -4-yl ) ethyl (4-(5-(1- cyanocyclopropane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3 - triazole -5- yl ) carbamate ( Compound 27 )

The synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethyl (4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate was followed as described in Example 49, Step 3, using 4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (0.0961 mmol) was used to replace 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid to obtain 4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Compound 27). (MS (m/z) 465.12 [M+H]+). 1H NMR (400 MHz, acetonitrile-d3) δ 9.00 - 8.89 (m, 1H), 8.88 - 8.75 (m, 1H), 8.55 (s, 1H), 8.20 (ddt, J = 9.1, 5.8, 2.8 Hz, 1H), 8.07 - 7.97 (m, 2H), 7.06 (s, 1H), 5.90 (q, J = 6.7 Hz, 1H), 3.96 (s, 3H), 3.18 - 3.06 (m, 1H), 3.02 - 2.79 (m, 3H), 2.31 (s, 3H), 2.10 (m, 1H), 1.53 (d, J = 6.7 Hz, 3H). Example 51 : Preparation of (R)-(4-(5-(3,3 -difluorocyclobutane -1 -carboxamido ) pyridin -2 - yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 28)

To a mixture of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5B) (0.07 mmol) in pyridine (0.5 mL) was added 3,3-difluorocyclobutanecarbonyl chloride (0.07 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 28). (MS ( m/z ) 494.1 [M+H] ⁺ ). 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.21 - 7.67 (m, 4H), 5.95 (s, 1H), 4.00 (s, 3H), 3.21 - 3.05 (m, 1H), 3.05 - 2.68 (m, 4H), 1.62 (s, 3H). Example 52 : Preparation of compounds 29 to 37

Compounds 29 to 37 were generally synthesized according to Scheme C, step 4. For example, (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-benzamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 29) was prepared as follows.

To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5A) (0.07 mmol) in pyridine (0.5 mL) was added benzyl chloride (0.07 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 h, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-(4-(5-benzamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester (Compound 29). (MS ( m/z ) 478.1 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.02 (s, 1H), 8.46 - 7.88 (m, 6H), 7.88 - 7.01 (m, 4H), 6.09 (q, J = 6.6 Hz, 1H), 3.99 (s, 3H), 1.62 (s, 3H).

Compounds 30-37 (Table 1) were prepared similarly according to Scheme C, Step 4 by reacting (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester (Intermediate 5A) (Example 21) following the general method described for compound 29 with the reagents listed in Table 1. Table 1 : Compounds prepared according to Scheme C , Step 4 . Compound No. Structure Reagent LCMS m/z 1H NMR Compound 29 (R)-(4-(5-benzylaminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 478.1 1H NMR (400 MHz, methanol-d4) δ 9.02 (s, 1H), 8.46 - 7.88 (m, 6H), 7.88 - 7.01 (m, 4H), 6.09 (q, J = 6.6 Hz, 1H), 3.99 (s, 3H), 1.62 (s, 3H). Compound 30 (R)-(4-(5-butyrylaminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 444.1 1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.53 - 7.71 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 2.43 (t, J = 7.4 Hz, 2H), 1.88 - 1.23 (m, 5H), 1.05 (t, J = 7.4 Hz, 3H). Compound 31 (R)-(4-(5-(2-methoxyacetamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 446.1 1H NMR (400 MHz, methanol-d4) δ 8.92 (s, 1H), 8.51 - 7.79 (m, 4H), 7.47 (s, 1H), 6.08 (d, J = 6.5 Hz, 1H), 4.12 (d, J = 2.5 Hz, 2H), 3.99 (d, J = 2.6 Hz, 3H), 3.54 (d, J = 2.5 Hz, 3H), 1.90 - 1.23 (m, 3H). Compound 32 (R)-(1-methyl-4-(5-(1-methylcyclopropane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 456.2 1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.53 - 7.69 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 6.8 Hz, 1H), 3.98 (s, 3H), 1.51 (s, 6H), 1.27 (q, J = 3.8 Hz, 2H), 0.82 - 0.73 (m, 2H). Compound 33 (R)-(1-methyl-4-(5-propionamidopyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 430.1 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.49 - 7.71 (m, 4H), 7.44 (dd, J = 7.7, 4.7 Hz, 1H), 6.08 (d, J = 6.6 Hz, 1H), 3.99 (s, 3H), 2.47 (q, J = 7.6 Hz, 2H), 1.84 - 1.38 (m, 3H), 1.25 (t, J = 7.6 Hz, 3H). Compound 34 (R)-(4-(5-(cyclopropanecarboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 442.1 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.53 - 7.73 (m, 4H), 7.44 (dd, J = 7.7, 4.7 Hz, 1H), 6.08 (d, J = 6.7 Hz, 1H), 3.98 (s, 3H), 1.83 (tt, J = 7.9, 4.6 Hz, 1H), 1.78 - 1.35 (m, 3H), 0.98 (ddt, J = 34.8, 8.0, 2.9 Hz, 4H). Compound 35 (R)-(4-(5-(cyclobutylcarboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 456.2 1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.55 - 7.76 (m, 4H), 7.44 (dd, J = 7.7, 4.8 Hz, 1H), 6.08 (d, J = 6.9 Hz, 1H), 3.98 (s, 3H), 2.51 - 2.33 (m, 2H), 2.26 (dddd, J = 10.2, 8.6, 6.8, 3.3 Hz, 2H), 2.17 - 2.02 (m, 1H), 2.02 - 1.88 (m, 1H), 1.57 (d, J = 31.9 Hz, 3H). Compound 36 (R)-(4-(5-(2,2-difluoroacetamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 452.1 1H NMR (400 MHz, methanol-d4) δ 8.93 (s, 1H), 8.43 - 7.72 (m, 4H), 7.47 (s, 1H), 6.52 - 5.83 (m, 2H), 3.99 (s, 3H), 1.58 (d, J = 26.9 Hz, 3H). Compound 37 (R)-(4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 492.2 1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.53 - 7.72 (m, 4H), 7.47 (s, 1H), 6.07 (d, J = 6.5 Hz, 1H), 3.99 (s, 3H), 3.15 (pd, J = 8.4, 3.2 Hz, 1H), 3.05 - 2.69 (m, 4H), 1.61 (s, 3H). Example 53 : Preparation of (R)-(4-(5-( aza -3- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3 - yl ) ethyl ester ( Compound 38)

To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5A) (0.06 mmol) in pyridine (0.5 mL) was added 1-Boc-aza-3-carboxylic acid (0.067 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.064 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 hours, at which time it was concentrated in vacuo and trifluoroacetic acid (0.2 mL) was added. The reaction mixture was allowed to stand with magnetic stirring for 0.5 h, at which time water (1 mL) and pyridine (0.5 mL) were added and the crude mixture was purified by HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(aza-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 38). (MS ( m/z ) 457.1 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.86 (s, 1H), 8.61 - 7.76 (m, 4H), 7.59 (d, J = 90.0 Hz, 1H), 6.07 (s, 1H), 4.53 - 4.18 (m, 4H), 4.00 (s, 3H), 3.87 (tt, J = 8.9, 7.1 Hz, 1H ), 1.66 (d, J = 36.7 Hz , 3H). Example 54 : Preparation of Compounds 39-184 and 195-296

Compounds 39-184 and 195-296 were generally synthesized according to Scheme C, step 4. For example, (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 39) was prepared as follows.

To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5B) (0.06 mmol) in pyridine (0.5 mL) were added 1-cyanocyclopropane-1-carboxylic acid (0.067 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.067 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 39). (MS ( m/z ) 469.1 [M+H] ⁺ ). ^1H NMR (400 MHz, Methanol- _d4 ) δ 8.79 (s, 1H), 8.33 - 7.46 (m, 4H), 5.95 (d, J = 6.9 Hz, 1H), 4.00 (s, 3H), 1.82 - 1.36 (m, 7H).

Compounds 40-160 and 195-206 (Table 2) were prepared similarly according to Scheme C, Step 4, following the general procedure described for compound 39 by reacting (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester, Intermediate 5A (Example 21) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid.

To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5B) (0.073 mmol) in pyridine (1.0 mL) were added 2-(trifluoromethyl)pyrimidine-5-carboxylic acid (0.082 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.087 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(1-methyl-4-(5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 251). (MS ( m/z ) 550.0 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.47 (s, 2H), 8.95 (s, 1H), 8.25 (dd, J = 8.6, 2.6 Hz, 1H), 8.03 (s, 1H), 7.98 (dd, J = 8.7, 0.7 Hz, 1H), 7.87 (s, 1H), 5.95 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H).

Compounds 161-165 and 207-284 (Table 2) were prepared similarly according to Scheme C, Step 4, following the general method described for compound 39 by reacting (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester, intermediate 5B (Example 22) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid.

To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5B) (0.073 mmol) in pyridine (0.5 mL) were added 3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid (0.080 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.080 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3-cyanobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 162). LCMS (( m/z ) 495.175 [M+H] ⁺ ). ^1H NMR (400 MHz, methanol-d ₄ ) δ 1H NMR (400 MHz, methanol-d 4 ) δ 8.83 (s, 1H), 8.22 - 7.58 (m, 4H), 5.94 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 2.64 (s, 6H), 1.61 (s, 3H).

Compounds 166-168, 285 and 288-290 (Table 2) were prepared similarly according to Scheme C, Step 4, following the general procedure described for compound 39 by reacting (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, intermediate 5C (Example 23) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid.

To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5C) (0.070 mmol) in pyridine (1.0 mL) were added 6-(trifluoromethyl)nicotinic acid (0.077 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.084 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(5-(6-(trifluoromethyl)nicotinamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 288). (MS ( m/z ) 565.0 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.26 (d, J = 2.1 Hz, 1H), 8.97 (s, 1H), 8.64 - 8.52 (m, 1H), 8.34 - 8.15 (m, 2H), 8.11 - 7.68 (m, 3H), 6.03 (d, J = 7.2 Hz, 1H), 4.00 (s, 3H), 1.60 (s, 3H).

To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5C) (0.054 mmol) in pyridine (2.0 mL) were added 1-(difluoromethyl)cyclopropane-1-carboxylic acid (0.081 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.107 mmol). The reaction mixture was stirred magnetically for 2 hours, concentrated and purified by HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(1-(difluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 166). (MS ( m/z ) 510.15 [M+H] ⁺ ). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.86 (bs, 1H), 9.63 (s, 1H), 8.73 (s, 1H), 8.42 (bs, 1H), 8.10 - 7.82 (m, 3H), 6.58 (t, J = 56.9 Hz, 1H), 5.83 (bs, 1H), 3.89 (s, 3H), 1.57 (bs, 3H), 1.43-1.27 (m, 2H), 1.24 - 1.03 (m, 2H).

Compounds 169-174 and 290-296 (Table 2) were prepared similarly according to Scheme C, Step 4 by reacting (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester, intermediate 5D (Example 24) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid following the general method described for compound 39.

Compounds 175-180 (Table 2) were prepared similarly according to Scheme C, Step 4 by reacting (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(5-fluoro-2-methylpyridin-3-yl)ethyl ester, intermediate 5E (Example 25) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid following the general method described for compound 39.

Compounds 181-182 (Table 2) were prepared similarly according to Scheme C, Step 4 by reacting 1-(2-chloro-6-fluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate, intermediate 5F (Example 34) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid following the general method described for compound 39.

Compounds 183-184 (Table 2) were prepared similarly according to Scheme C, Step 4 by reacting (R)-(4-(5-amino-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester, intermediate 7B (Example 18) with the reagents listed in Table 2 instead of 1-cyanocyclopropane-1-carboxylic acid following the general method described for compound 39.

Compounds 201-204, 245-246 and 265-270 (Table 2) were prepared using racemic mixtures of the reagents listed in Table 2 and purified by chiral SFC purification to give single stereoisomers.surface 2 ：According to the process C , step 4 Prepared compounds. Compound No. Structure Reagent LCMS m/z 1H NMR Compound 39 (R)-(4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 469.1 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.33 - 7.46 (m, 4H), 5.95 (d, J = 6.9 Hz, 1H), 4.00 (s, 3H), 1.82 - 1.36 (m, 7H). Compound 40 (R)-(4-(5-(1-chlorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 476.3 1H NMR (400 MHz, methanol-d4) δ 8.87 (s, 1H), 8.48 - 7.76 (m, 4H), 7.46 (s, 1H), 6.08 (q, J = 6.5 Hz, 1H), 3.99 (s, 3H), 1.76 - 1.70 (m, 2H), 1.64 (d, J = 28.0 Hz, 3H), 1.46 - 1.38 (m, 2H). Compound 41 (R)-(4-(5-(6,6-difluorospiro[3.3]heptane-2-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 532.2 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.54 - 7.71 (m, 4H), 7.46 (s, 1H), 6.07 (d, J = 7.1 Hz, 1H), 3.98 (s, 3H), 3.26 (p, J = 8.4 Hz, 1H), 2.69 (td, J = 12.2, 2.6 Hz, 2H), 2.64 - 2.45 (m, 4H), 2.45 - 2.31 (m, 2H), 1.61 (s, 3H). Compound 42 (R)-(4-(5-(2-oxospiro[3.3]heptane-6-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 498.2 1H NMR (400 MHz, methanol-d4) δ 8.83 (s, 1H), 8.52 - 7.74 (m, 4H), 7.46 (s, 1H), 6.07 (d, J = 7.0 Hz, 1H), 4.76 (s, 2H), 4.70 (s, 2H), 3.98 (s, 3H), 3.11 (p, J = 7.9 Hz, 1H), 2.56 (d, J = 8.0 Hz, 4H), 1.61 (s, 3H). Compound 43 (R)-(4-(5-(1,1-dioxothiocyclobutane-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 506.2 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.48 - 7.73 (m, 4H), 7.47 (s, 1H), 6.07 (d, J = 7.2 Hz, 1H), 4.63 - 4.45 (m, 2H), 4.45 - 4.25 (m, 2H), 3.55 (tt, J = 9.8, 7.6 Hz, 1H), 1.61 (s, 3H). Compound 44 (R)-(1-methyl-4-(5-(3-(oxo-3-yl)bicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 524.2 1H NMR (400 MHz, methanol-d4) δ 8.92 (s, 1H), 8.46 - 7.70 (m, 4H), 7.47 (s, 1H), 6.08 (d, J = 7.1 Hz, 1H), 4.81 (dd, J = 7.9, 6.0 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 3.99 (s, 3H), 3.18 (tt, J = 8.0, 5.9 Hz, 1H), 2.15 (s, 6H), 1.61 (s, 3H). Compound 45 (R)-(4-(5-(3-(difluoromethyl)bicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 518.2 1H NMR (400 MHz, methanol-d4) δ 8.91 (s, 1H), 8.53 - 7.79 (m, 4H), 7.46 (s, 1H), 6.25 - 5.60 (m, 2H), 3.99 (s, 3H), 2.26 (s, 6H), 1.61 (s, 3H). Compound 46 (R)-(4-(5-(3-methoxybicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 498.1 1H NMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 8.47 - 7.76 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 6.9 Hz, 1H), 3.99 (s, 3H), 3.36 (s, 3H), 2.28 (s, 6H), 1.61 (s, 3H). Compound 47 (R)-(1-methyl-4-(5-(3-methylbicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 482.2 1H NMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 8.48 - 7.71 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 7.0 Hz, 1H), 3.98 (s, 3H), 2.05 (s, 6H), 1.61 (s, 3H), 1.26 (s, 3H). Compound 48 (R)-(1-methyl-4-(5-(1-(trifluoromethyl)cyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 524.2 1H NMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 8.46 - 7.74 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 6.7 Hz, 1H), 3.99 (s, 3H), 2.90 - 2.69 (m, 2H), 2.60 (ddt, J = 9.5, 7.7, 5.7 Hz, 2H), 2.20 - 1.96 (m, 2H), 1.61 (s, 3H). Compound 49 (R)-(4-(5-(2,2-dimethylcyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 470.2 1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.43 - 7.68 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 6.5 Hz, 1H), 3.98 (s, 3H), 1.82 - 1.43 (m, 4H), 1.30 - 1.21 (m, 6H), 1.21 - 1.16 (m, 1H), 0.90 (dd, J = 7.9, 4.3 Hz, 1H). Compound 50 (R)-(4-(5-((1S,2S)-2-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 467.0 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.55 - 7.00 (m, 5H), 6.08 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 2.48 (ddd, J = 8.6, 5.9, 4.2 Hz, 1H), 2.23 - 2.03 (m, 1H), 1.58 (dddd, J = 14.8, 8.6, 6.0, 4.6 Hz, 5H). Compound 51 (R)-(4-(5-((1R,2R)-2-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 467.0 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.52 - 7.18 (m, 5H), 6.08 (d, J = 6.8 Hz, 1H), 3.99 (s, 3H), 2.48 (ddd, J = 8.6, 5.9, 4.3 Hz, 1H), 2.24 - 2.02 (m, 1H), 1.59 (dddd, J = 16.1, 8.5, 6.0, 4.6 Hz, 5H). Compound 52 (R)-(4-(5-((1R,2S)-2-fluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 460.1 1H NMR (400 MHz, methanol-d4) δ 8.82 (s, 1H), 8.48 - 7.73 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 6.7 Hz, 1H), 4.96 (ddd, J = 6.2, 3.3, 1.6 Hz, 1H), 2.29 (dddd, J = 17.3, 10.5, 6.6, 1.6 Hz, 1H), 1.91 - 1.15 (m, 5H). Compound 53 (R)-(4-(5-((1S,2S)-2-fluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 460.2 1H NMR (400 MHz, methanol-d4) δ 8.86 (s, 1H), 8.61 - 7.72 (m, 4H), 7.47 (s, 1H), 6.08 (d, J = 6.7 Hz, 1H), 4.97 (td, J = 6.2, 3.7 Hz, 1H), 3.99 (s, 3H), 2.09 - 2.01 (m, 1H), 1.82 (dtd, J = 23.0, 7.1, 3.7 Hz, 1H), 1.61 (s, 3H), 1.23 (dddd, J = 12.7, 9.2, 7.0, 6.0 Hz, 1H). Compound 54 (R)-(1-methyl-4-(5-(oxo-2-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 458.2 1H NMR (400 MHz, methanol-d4) δ 8.96 (s, 1H), 8.48 - 7.77 (m, 4H), 7.47 (s, 1H), 6.08 (d, J = 6.5 Hz, 1H), 5.21 (ddd, J = 9.2, 6.7, 0.8 Hz, 1H), 4.86 - 4.73 (m, 2H), 3.99 (s, 3H), 3.14 (dtd, J = 11.5, 8.9, 6.5 Hz, 1H), 2.79 (ddtd, J = 11.4, 9.2, 6.9, 2.6 Hz, 1H), 1.61 (s, 3H). Compound 55 (R)-(1-methyl-4-(5-(1-(trifluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 510.2 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.58 - 7.72 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 6.8 Hz, 1H), 3.99 (s, 3H), 1.92 - 1.16 (m, 7H). Compound 56 (R)-(4-(5-((1R,2R)-2-fluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 460.1 1H NMR (400 MHz, methanol-d4) δ 8.87 (s, 1H), 8.51 - 7.71 (m, 4H), 7.46 (s, 1H), 6.08 (q, J = 6.6 Hz, 1H), 4.98 (td, J = 6.2, 3.7 Hz, 1H), 3.99 (s, 3H), 2.11 - 2.01 (m, 1H), 1.82 (dtd, J = 23.0, 7.1, 3.7 Hz, 1H), 1.62 (s, 3H), 1.23 (dddd, J = 12.8, 9.3, 7.0, 6.0 Hz, 1H). Compound 57 (R)-(1-methyl-4-(5-(oxo-3-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 458.2 1H NMR (400 MHz, methanol-d4) δ 8.86 (s, 1H), 8.53 - 7.77 (m, 4H), 7.47 (s, 1H), 6.07 (s, 1H), 4.92 (q, J = 6.2, 4.3 Hz, 4H), 4.02 (d, J = 30.2 Hz, 4H), 1.58 (d, J = 28.0 Hz, 3H). Compound 58 (R)-(1-methyl-4-(5-(nicotinylamino)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 479.2 1H NMR (400 MHz, methanol-d4) δ 9.16 (dd, J = 2.3, 0.9 Hz, 1H), 9.02 (s, 1H), 8.77 (dd, J = 4.9, 1.6 Hz, 1H), 8.42 (ddd, J = 8.0, 2.3, 1.6 Hz, 1H), 8.32 (s, 1H), 8.25 - 7.83 (m, 3H), 7.64 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 7.49 (s, 1H), 6.09 (d, J = 6.8 Hz, 1H), 4.00 (s, 3H), 1.62 (s, 3H). Compound 59 (R)-(4-(5-(2-cyanoacetamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 441.1 1H NMR (400 MHz, methanol-d4) δ 8.82 (s, 1H), 8.52 - 7.74 (m, 4H), 7.44 (dd, J = 7.8, 4.8 Hz, 1H), 6.08 (d, J = 6.9 Hz, 1H), 3.99 (s, 3H), 3.84 (s, 2H), 1.95 - 1.09 (m, 3H). Compound 60 (R)-(4-(5-(1-fluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 460.1 1H NMR (400 MHz, methanol-d4) δ 8.93 (s, 1H), 8.57 - 7.74 (m, 4H), 7.47 (s, 1H), 6.08 (q, J = 6.6 Hz, 1H), 3.99 (s, 3H), 1.84 - 1.34 (m, 7H). Compound 61 (R)-(4-(5-(isonicotinoylamino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 479.1 1H NMR (400 MHz, methanol-d4) δ 9.02 (s, 1H), 8.87 - 8.70 (m, 2H), 8.48 - 7.77 (m, 6H), 7.49 (s, 1H), 6.09 (d, J = 6.7 Hz, 1H), 4.00 (s, 3H), 1.62 (s, 3H). Compound 62 (R)-(4-(5-((1r,3R)-3-fluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 474.2 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.50 - 7.77 (m, 4H), 6.08 (d, J = 6.2 Hz, 1H), 5.48 - 5.07 (m, 1H), 3.99 (s, 3H), 2.78 - 2.38 (m, 4H), 1.61 (s, 3H). Compound 63 (R)-(4-(5-(2,2-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 492.1 1H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.57 - 7.73 (m, 4H), 7.47 (s, 1H), 6.08 (q, J = 6.5 Hz, 1H), 3.99 (s, 3H), 3.93 - 3.77 (m, 1H), 2.64 (dddd, J = 13.4, 11.8, 9.3, 7.6 Hz, 2H), 2.33 (tt, J = 12.0, 7.6 Hz, 1H), 2.11 - 2.00 (m, 1H), 1.61 (s, 3H). Compound 64 (R)-(4-(5-(3-cyanobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 493.2 1H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.51 - 7.74 (m, 4H), 7.46 (s, 1H), 6.07 (d, J = 6.4 Hz, 1H), 3.98 (s, 3H), 2.64 (s, 6H), 1.61 (s, 3H). Compound 65 (R)-(4-(5-((S)-2,2-difluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 478.1 1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.53 - 7.74 (m, 4H), 7.47 (s, 1H), 6.08 (d, J = 7.0 Hz, 1H), 2.76 (ddd, J = 13.1, 10.8, 7.7 Hz, 1H), 2.16 (dtd, J = 12.7, 7.7, 6.1 Hz, 1H), 1.90 (dddd, J = 12.6, 10.8, 7.8, 4.9 Hz, 1H), 1.61 (s, 3H). Compound 66 (R)-(4-(5-(1-cyanocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 481.2 1H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.46 - 7.75 (m, 4H), 7.47 (s, 1H), 6.08 (d, J = 6.9 Hz, 1H), 3.99 (s, 3H), 2.89 (dtd, J = 11.0, 7.4, 1.5 Hz, 2H), 2.76 - 2.64 (m, 2H), 2.30 (dtt, J = 11.6, 9.2, 7.4 Hz, 1H), 2.21 - 2.02 (m, 1H), 1.61 (s, 3H). Compound 67 (R)-(4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 467.1 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.50 - 7.76 (m, 4H), 7.46 (s, 1H), 6.30 - 5.74 (m, 1H), 3.99 (s, 3H), 1.84 - 1.38 (m, 7H). Compound 68 (R)-(4-(5-(bicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 468.2 1H NMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 8.47 - 7.71 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 6.8 Hz, 1H), 3.98 (s, 3H), 2.53 (s, 1H), 2.22 (s, 6H), 1.61 (s, 3H). Compound 69 (R)-(4-(5-((1S,2R)-2-fluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 460.2 1H NMR (400 MHz, methanol-d4) δ 8.82 (s, 1H), 8.48 - 7.71 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 6.7 Hz, 1H), 4.96 (ddd, J = 6.2, 3.4, 1.6 Hz, 1H), 3.98 (s, 3H), 2.29 (dddd, J = 17.3, 10.4, 6.6, 1.6 Hz, 1H), 1.89 - 1.16 (m, 5H). Compound 70 (R)-(4-(5-(3-fluorobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 486.2 1H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.47 - 7.71 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 6.9 Hz, 1H), 3.99 (s, 3H), 2.47 (d, J = 2.4 Hz, 6H), 1.61 (s, 3H). Compound 71 (R)-(4-(5-((1S,3S)-3-fluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 474.2 1H NMR (400 MHz, methanol-d4) δ 8.86 (s, 1H), 8.54 - 7.79 (m, 4H), 7.47 (s, 1H), 6.08 (d, J = 7.0 Hz, 1H), 5.12 - 4.89 (m, 1H), 2.84 - 2.71 (m, 1H), 2.71 - 2.58 (m, 2H), 2.50 (ddddd, J = 19.4, 11.9, 9.6, 7.6, 2.0 Hz, 2H), 1.61 (s, 3H). Compound 72 (R)-(1-methyl-4-(5-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 536.2 1H NMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 8.44 - 7.71 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 6.5 Hz, 1H), 3.99 (s, 3H), 2.39 (s, 6H), 1.61 (s, 3H). Compound 73 (R)-(1-methyl-4-(5-(spiro[3.3]heptane-2-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 496.2 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.46 - 7.69 (m, 4H), 7.47 (s, 1H), 6.07 (d, J = 6.9 Hz, 1H), 3.98 (s, 3H), 3.16 (p, J = 8.5 Hz, 1H), 2.39 - 2.20 (m, 4H), 2.14 (ddd, J = 7.3, 5.9, 1.2 Hz, 2H), 1.99 (dd, J = 8.5, 5.9 Hz, 2H), 1.92 - 1.79 (m, 2H), 1.61 (s, 3H). Compound 74 (R)-(4-(5-(1-cyanospiro[2.3]hexane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 507.2 1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.52 - 7.73 (m, 4H), 7.46 (s, 1H), 6.25 - 5.91 (m, 1H), 3.99 (s, 3H), 2.65 (ddd, J = 12.0, 9.3, 6.8 Hz, 1H), 2.40 - 2.06 (m, 6H), 1.90 - 1.36 (m, 4H). Compound 75 (R)-(4-(5-(3-cyclopropylpropynylamino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 466.2 1H NMR (400 MHz, methanol-d4) δ 8.83 (s, 1H), 8.49 - 7.69 (m, 4H), 7.46 (s, 1H), 6.07 (d, J = 6.7 Hz, 1H), 3.98 (s, 3H), 1.91 - 1.33 (m, 4H), 1.07 - 1.00 (m, 2H), 0.95 - 0.86 (m, 2H). Compound 76 (R)-(4-(5-(but-2-ynylamino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 440.0 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.48 - 7.75 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 6.7 Hz, 1H), 3.98 (s, 3H), 2.08 (s, 3H), 1.61 (s, 3H). Compound 77 (R)-(4-(5-(dispiro[3.1.36.14]decane-2-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 537.2 1H NMR (400 MHz, methanol-d4) δ 8.83 (s, 1H), 8.52 - 7.70 (m, 4H), 7.46 (s, 1H), 6.07 (d, J = 7.0 Hz, 1H), 3.98 (s, 3H), 3.19 (q, J = 8.5 Hz, 1H), 2.34 (td, J = 10.0, 1.7 Hz, 2H), 2.21 (dd, J = 11.9, 8.6 Hz, 2H), 2.15 (s, 2H), 2.03 - 1.92 (m, 6H), 1.89 - 1.77 (m, 2H), 1.61 (s, 3H). Compound 78 (R)-(1-methyl-4-(5-(2-(trifluoromethyl)spiro[3.3]heptane-2-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 564.1 1H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.53 - 7.74 (m, 4H), 7.46 (s, 1H), 6.08 (d, J = 6.8 Hz, 1H), 3.99 (s, 3H), 2.77 (d, J = 13.3 Hz, 2H), 2.62 (d, J = 13.8 Hz, 2H), 2.10 (dt, J = 21.0, 7.5 Hz, 4H), 1.92 - 1.81 (m, 2H), 1.61 (s, 3H). Compound 79 (R)-(4-(5-(2-cyanospiro[3.3]heptane-2-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 521.2 1H NMR (400 MHz, methanol-d4) δ 8.86 (s, 1H), 8.46 - 7.74 (m, 4H), 7.47 (s, 1H), 6.08 (d, J = 6.8 Hz, 1H), 3.99 (s, 3H), 2.96 - 2.80 (m, 2H), 2.80 - 2.58 (m, 2H), 2.28 (t, J = 7.5 Hz, 2H), 2.07 (dd, J = 8.7, 6.1 Hz, 2H), 1.97 - 1.85 (m, 2H), 1.61 (s, 3H). Compound 80 (R)-(4-(5-(6-cyanospiro[3.3]heptane-2-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 521.3 1H NMR (400 MHz, methanol-d4) δ 8.83 (s, 1H), 8.49 - 7.74 (m, 4H), 7.46 (s, 1H), 6.07 (d, J = 7.0 Hz, 1H), 3.98 (s, 3H), 3.18 (h, J = 8.2 Hz, 2H), 2.60 (ddd, J = 11.6, 8.4, 3.3 Hz, 1H), 2.42 (dddd, J = 29.1, 15.3, 11.7, 7.0 Hz, 7H), 1.61 (s, 3H). Compound 81 (R)-(4-(5-(6-fluorospiro[3.3]heptane-2-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 514.3 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.58 - 7.71 (m, 4H), 7.47 (s, 1H), 6.07 (d, J = 6.8 Hz, 1H), 5.00 (p, J = 6.7 Hz, 1H), 3.98 (s, 3H), 3.24 (p, J = 8.4 Hz, 1H), 2.60 (dq, J = 12.5, 6.4 Hz, 1H), 2.53 - 2.34 (m, 3H), 2.34 - 2.08 (m, 4H), 1.61 (s, 3H). Compound 82 (R)-(4-(5-(3-chlorobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 502.2 1H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.52 - 7.72 (m, 4H), 7.46 (s, 1H), 6.07 (d, J = 7.0 Hz, 1H), 3.98 (s, 3H), 2.54 (s, 6H), 1.61 (s, 3H). Compound 83 (R)-(1-methyl-4-(5-(3-oxocyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 470.2 1H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.54 - 7.72 (m, 4H), 7.47 (s, 1H), 6.08 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 3.57 - 3.34 (m, 5H), 1.61 (s, 3H). Compound 84 (R)-(4-(5-(3,3-dimethylcyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 484.2 1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.55 - 7.77 (m, 4H), 7.47 (s, 1H), 6.08 (d, J = 6.7 Hz, 1H), 3.98 (s, 3H), 3.25 (q, J = 8.7 Hz, 1H), 2.17 (ddd, J = 10.8, 9.2, 1.9 Hz, 2H), 2.09 - 1.96 (m, 2H), 1.61 (s, 3H), 1.26 (s, 3H), 1.16 (s, 3H). Compound 85 (R)-(4-(5-((3R,5r)-1,1-difluorospiro[2.3]hexane-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 518.1 1H NMR (400 MHz, methanol-d4) δ 8.87 (s, 1H), 8.46 - 7.72 (m, 4H), 7.48 (s, 1H), 6.08 (d, J = 6.7 Hz, 1H), 3.99 (s, 3H), 3.55 - 3.41 (m, 1H), 2.71 (dd, J = 12.5, 6.6 Hz, 2H), 2.39 (t, J = 11.1 Hz, 2H), 1.61 (s, 3H), 1.36 (t, J = 8.5 Hz, 2H). Compound 86 (R)-(4-(5-((3S,5s)-1,1-difluorospiro[2.3]hexane-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 518.7 1H NMR (400 MHz, methanol-d4) δ 8.86 (s, 1H), 8.53 - 7.73 (m, 4H), 7.47 (s, 1H), 6.08 (d, J = 7.5 Hz, 1H), 3.99 (s, 3H), 3.41 (t, J = 8.7 Hz, 1H), 2.66 - 2.46 (m, 4H), 1.61 (s, 3H), 1.30 (t, J = 8.5 Hz, 2H). Compound 87 (R)-(4-(5-(5-cyanospiro[2.3]hexane-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 507.2 1H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.55 - 7.72 (m, 4H), 7.47 (s, 1H), 6.31 - 5.75 (m, 1H), 3.99 (s, 3H), 3.05 (dd, J = 11.7, 1.7 Hz, 2H), 2.77 (dt, J = 11.1, 1.6 Hz, 2H), 1.62 (s, 3H), 0.78 - 0.64 (m, 2H), 0.64 - 0.47 (m, 2H). Compound 88 (R)-(1-methyl-4-(5-(spiro[2.3]hexane-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 482.3 1H NMR (400 MHz, methanol-d4) δ 8.87 (s, 1H), 8.54 - 7.74 (m, 4H), 7.47 (s, 1H), 6.08 (d, J = 6.7 Hz, 1H), 3.99 (s, 3H), 3.48 (tt, J = 8.9, 7.6 Hz, 1H), 2.69 - 2.54 (m, 2H), 2.36 - 2.20 (m, 2H), 1.61 (s, 3H), 0.64 - 0.31 (m, 4H). Compound 89 (R)-(4-(5-(1-cyanospiro[2.4]heptane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 521.2 1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.47 - 7.70 (m, 4H), 7.47 (s, 1H), 6.08 (d, J = 6.9 Hz, 1H), 3.99 (s, 3H), 2.26 - 2.07 (m, 2H), 1.95 - 1.44 (m, 11H). Compound 90 (R)-(4-(5-((S)-2,2-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 492.1 1H NMR (400 MHz, acetonitrile-d3) δ 7.50 (s, 1H), 7.05 - 6.42 (m, 4H), 6.09 (s, 1H), 4.71 (d, J = 6.9 Hz, 1H), 2.56 - 2.37 (m, 1H), 1.36 - 1.15 (m, 2H), 0.95 (d, J = 11.4 Hz, 1H), 0.65 (s, 1H), 0.24 (s, 3H). Compound 91 (R)-(4-(5-((R)-2,2-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 492.0 1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.40 - 7.77 (m, 4H), 7.44 (s, 1H), 6.06 (d, J = 6.9 Hz, 1H), 3.97 (s, 3H), 3.92 - 3.72 (m, 1H), 2.71 - 2.50 (m, 2H), 2.30 (d, J = 11.4 Hz, 1H), 2.00 (s, 1H), 1.59 (s, 3H). Compound 92 (R)-(4-(5-(1-aminoformylcyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 485.1 1H NMR (400 MHz, acetonitrile-d3) δ 11.63 (s, 1H), 8.99 (d, J = 2.5 Hz, 1H), 8.57 (s, 1H), 8.34 (dd, J = 4.8, 1.9 Hz, 1H), 8.23 (dd, J = 8.8, 2.5 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.92 (s, 1H), 7.40 (d, J = 6.6 Hz, 1H), 6.33 (s, 1H), 6.04 (q, J = 6.6 Hz, 2H), 3.96 (s, 3H), 1.70 (q, J = 4.4 Hz, 2H), 1.58 (d, J = 6.5 Hz, 3H), 1.52 (q, J = 4.4 Hz, 2H). Compound 93 (R)-(4-(5-(3-oxo-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 483.1 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.95 (s, 1H), 8.78 (s, 1H), 8.36 (s, 1H), 8.07 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 - 7.90 (m, 2H), 7.61- 7.45 (m, 1H), 5.89 (d, J = 7.1 Hz, 1H), 5.09 - 4.93 (m, 4H), 3.89 (s, 3H), 1.53 (s, 3H). Compound 94 (R)-(1-methyl-4-(5-(1-(pyridin-3-yl)cyclopropane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 519.1 1H NMR (400 MHz, DMSO-d6) δ 9.81 (brs, 1H), 9.43 (s, 1H), 8.72 (s, 1H), 8.65 (d, J = 2.3 Hz, 1H), 8.53 (dd, J = 4.8, 1.6 Hz, 1H), 8.35 (s, 1H), 7.99 (dd, J = 8.7, 2.6 Hz, 1H), 7.92 - 7.75 (m, 2H), 7.50 - 7.40 (m, 3H), 5.86 (m, 1H), 3.87 (s, 3H), 1.61-1.57 (m, 4H), 1.25-1,24 (m, 3H). Compound 95 (R)-(4-(5-(4-cyanotetrahydro-2H-pyran-4-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 511.2 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.85 (brs,1H), 8.80 (s, 1H), 8.36 (s, 1H), 8.08 (dd, J = 8.6, 2.5 Hz, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.60-7.45 (m, 1H), 5.95 - 5.83 (m, 1H), 4.00 (dt, J = 12.2, 3.4 Hz, 2H), 3.88 (s, 3H), 3.60 (ddd, J = 12.4, 9.9, 3.8 Hz, 2H), 2.26 - 2.09 (m, 4H), 1.65-1.40 (m, 3H) Compound 96 (R)-(4-(5-(3-ethyloxy-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 486.2 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.73 (s, 1H), 8.85- 8.78 (m, 1H), 8.40-8.32 (m, 1H), 8.07 (dd, J = 8.6, 2.5 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.62-7.45 (m, 2H), 5.92-5.80 (m, 1H), 4.84 (d, J = 6.2 Hz, 2H), 4.42 (d, J = 6.2 Hz, 2H), 3.88 (s, 3H), 2.10 (q, J = 7.4 Hz, 2H), 1.75-1.45 (m, 3H), 0.87 (t, J = 7.4 Hz, 3H). Compound 97 (R)-(1-methyl-4-(5-(3-methyloxy-3-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 472.2 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.85 (s, 1H), 8.81 (s, 1H), 8.45 - 8.35 (m, 1H), 8.08 (dd, J = 8.6, 2.5 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.65 - 7.43 (m, 2H), 5.95- 5.82 (m, 1H), 4.88 (d, J = 6.0 Hz, 2H), 4.39 (d, J = 6.1 Hz, 2H), 3.89 (s, 3H), 1.65 (s, 3H), 1.55 (s, 3H) Compound 98 (R)-(4-(5-(6-cyanopyridinylamino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 504.1 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.11 (s, 1H), 8.51 (d, J = 7.7 Hz, 1H), 8.38 - 8.22 (m, 4H), 8.16 - 8.08 (m, 2H), 7.98 (d, J = 8.7 Hz, 1H), 6.07 (s, 1H), 3.98 (s, 3H), 1.61 (s, 3H). Compound 99 (R)-(4-(5-(6-cyanonicotinamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 504.2 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.25 (dd, J = 2.2, 0.8 Hz, 1H), 9.00 (s, 1H), 8.52 (dd, J = 8.1, 2.2 Hz, 1H), 8.30 (s, 1H), 8.21 (dd, J = 8.6, 2.6 Hz, 1H), 8.06 (dd, J = 8.1, 0.9 Hz, 1H), 8.00 - 7.37 (m, 3H), 6.07 (d, J = 6.9 Hz, 1H), 3.98 (s, 3H), 1.60 (s, 3H). Compound 100 (R)-(4-(5-(2-cyanoisonicotinamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 504.2 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.00 (s, 1H), 8.93 (dd, J = 5.1, 0.9 Hz, 1H), 8.40 (dd, J = 1.7, 0.9 Hz, 1H), 8.30 (s, 1H), 8.21 (dd, J = 8.6, 2.6 Hz, 1H), 8.18 - 8.04 (m, 2H), 7.97 (d, J = 8.6 Hz, 1H), 7.56 - 7.39 (m, 1H), 6.07 (s, 1H), 3.98 (s, 3H), 1.60 (s, 3H). Compound 101 (R)-(1-methyl-4-(5-(3-methylisoxanthamide)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 493.0 1H NMR (400 MHz, methanol-d4) δ 8.94 (s, 1H), 8.56 (s, 1H), 8.54 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.16 (dd, J = 8.6, 2.6 Hz, 1H), 8.06 (s, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 5.0 Hz, 1H), 7.47 (s, 1H), 6.07 (d, J = 6.2 Hz, 1H), 3.98 (s, 3H), 2.50 (s, 3H), 1.60 (s, 3H). Compound 102 (R)-(1-methyl-4-(5-(2-methylisoxanthamide)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 493.0 1H NMR (400 MHz, methanol-d4) δ 9.00 (s, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.30 (s, 1H), 8.20 (dd, J = 8.7, 2.6 Hz, 1H), 8.07 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.82 (s, 1H), 7.73 (dd, J = 5.3, 1.6 Hz, 1H), 7.47 (s, 1H), 6.07 (d, J = 6.8 Hz, 1H), 3.98 (s, 3H), 2.66 (s, 3H),1.60 (s, 3H). Compound 103 (R)-(4-(5-(2-chloroisocyanamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 513.2 1H NMR (400 MHz, methanol-d4) δ 9.00 (s, 1H), 8.59 (dd, J = 5.1, 0.7 Hz, 1H), 8.30 (s, 1H), 8.20 (dd, J = 8.7, 2.6 Hz, 1H), 8.07 (s, 1H), 8.03 - 7.90 (m, 2H), 7.87 (dd, J = 5.1, 1.5 Hz, 1H), 7.47 (s, 1H), 6.07 (d, J = 6.8 Hz, 1H), 3.98 (s, 3H), 1.60 (s, 3H). Compound 104 (R)-(4-(5-(2-oxabicyclo[2.1.1]hexane-4-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 484.1 1H NMR (400 MHz, DMSO-d6) δ 10.04-9.54 (m, 2H), 8.86 (bs, 1H), 8.36 (bs, 1H), 8.20-7.83 (m, 3H), 7.53 (bs, 1H), 5.88 (bs, 1H), 4.52 (s, 1H), 3.98-3.75 (m, 5H), 2.28-2.15 (m, 2H), 1.87-1.74 (m, 2H), 1.56 (bs, 3H). Compound 105 (R)-(4-(5-(2-oxabicyclo[2.1.1]hexane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 484.2 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.85 (bs, 1H), 8.93 (bs, 1H), 8.36 (bs, 1H), 8.21 (dd, J = 8.6, 2.5 Hz, 1H), 8.04 (bs, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.55 (bs, 1H), 5.87 (bs, 1H), 3.99-3.75 (m, 5H), 3.00 (t, J = 3.3 Hz, 1H), 2.27 - 2.11 (m, 2H), 1.77 - 1.30 (m, 5H). Compound 106 (R)-(4-(5-(1H-imidazole-4-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 482.1 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.83 (bs, 1H), 8.88 (s, 1H), 8.36 (bs, 1H), 8.16 (dd, J = 8.6, 2.6 Hz, 1H), 8.09 - 7.73 (m, 4H), 7.52 (bs, 1H), 5.87 (bs, 1H), 3.97-3.80 (m, 6H), 1.51 (bs, 3H). Compound 107 (R)-(4-(5-(3,3-difluoropropionamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 468.2 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.70 (s, 1H), 10.24 (s, 1H), 9.83 (bs, 1H), 9.06 (s, 1H), 8.48-8.25 (m, 2H), 8.06 (bs, 1H), 7.96-7.78 (m, 3H), 7.60 (bs, 1H), 5.88 (bs, 1H), 3.88 (s, 3H), 1.57 (bs, 3H). Compound 108 (R)-(4-(5-(3-hydroxy-3-methylcyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 466.1 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.82 (bs, 1H), 8.75 (bs, 1H), 8.36 (bs, 1H), 8.04 (dd, J = 8.6, 2.5 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.53 (bs, 2H), 6.42 (tt, J = 55.8, 4.8 Hz, 1H), 5.87 (bs, 1H), 3.88 (s, 3H), 3.13 (td, J = 16.8, 4.8 Hz, 2H), 1.56 (bs, 3H). Compound 109 (R)-(4-(5-(3-hydroxy-3-methylcyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 486.1 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.83 (bs, 1H), 8.77 (bs, 1H), 8.36 (bs, 1H), 8.10-7.99 (m, 2H), 7.88 (d, J = 8.6 Hz, 1H), 7.53 (bs, 1H), 5.87 (bs, 1H), 5.10 (s, 1H), 3.87 (s, 3H), 2.80-2.71 (m, 1H), 2.32 - 2.17 (m, 2H), 2.15-2.10 (m, 2H), 1.55 (bs, 3H), 1.29 (s, 3H). Compound 110 (R)-(4-(5-(1-(fluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 474.2 1H NMR (400 MHz, DMSO-d6) δ 9.83 (bs, 1H), 9.62 (s, 1H), 8.81 (bs, 1H), 8.36 (bs, 1H), 8.08 (dd, J = 8.6, 2.5 Hz, 2H), 7.90 (d, J = 8.6 Hz, 1H), 7.53 (bs, 1H), 5.87 (bs, 1H), 4.71 (d, J = 48.5 Hz, 2H), 3.87 (s, 3H), 1.56 (bs, 3H), 1.40 - 1.27 (m, 2H), 1.01 (qd, J = 4.3, 1.1 Hz, 2H). Compound 111 (R)-(4-(5-(4-hydroxy-4-methylpentan-2-ylamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 484.2 1H NMR (400 MHz, DMSO-d6) δ 10.92 (bs, 1H), 9.84 (bs, 1H), 8.76 (bs, 1H), 8.36 (bs, 1H), 8.20-7.85 (m, 3H), 7.54 (bs, 1H), 5.87 (bs, 1H), 5.75 (s, 1H), 3.88 (s, 3H), 1.67-1.37 (m, 9H). Compound 112 (R)-(1-methyl-4-(5-(1-methyl-1H-pyrazole-4-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 482.1 1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.85 (bs, 1H), 8.93 (bs, 1H), 8.36 (s, 2H), 8.22 - 7.98 (m, 3H), 7.94 (d, J = 8.6 Hz, 1H), 7.55 (bs, 1H), 5.88 (bs, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 1.57 (bs, 3H). Compound 113 (R)-(4-(5-(1H-pyrazole-4-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 468.2 1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 10.06 (s, 1H), 9.87 (bs, 1H), 8.94 (bs, 1H), 8.36 (bs, 2H), 8.23-7.96 (m, 2H), 7.94 (d, J = 8.6 Hz, 1H), 7.55 (bs, 1H), 5.88 (bs, 1H), 3.88 (s, 3H), 1.57 (bs, 3H). Compound 114 (R)-(4-(5-(4-fluorobicyclo[2.2.2]octane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 527.9 1H NMR (400 MHz, DMSO-d6) δ 9.84 (bs, 1H), 9.48 (s, 1H), 8.80 (bs, 1H), 8.35 (bs, 1H), 8.20-7.92 (m, 2H), 7.87 (d, J = 8.7 Hz, 1H), 7.53 (bs, 1H), 5.87 (bs, 1H), 3.87 (s, 3H), 2.10-1.97 (m, 6H), 1.89-1.75 (m, 6H), 1.56 (bs, 3H). Compound 115 (R)-(4-(5-(4-hydroxybicyclo[2.2.2]octane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 525.9 1H NMR (400 MHz, DMSO-d6) δ 9.84 (bs, 1H), 9.40 (s, 1H), 8.80 (bs, 1H), 8.35 (bs, 1H), 8.15-7.92 (m, 2H), 7.86 (d, J = 8.7 Hz, 1H), 7.53 (bs, 1H), 5.87 (bs, 1H), 4.36 (s, 1H), 3.87 (s, 3H), 2.01 - 1.78 (m, 6H), 1.78 - 1.31 (m, 9H). Compound 116 (R)-(4-(5-(1-(difluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 491.9 1H NMR (400 MHz, DMSO-d6) δ 9.85 (bs, 1H), 9.64 (s, 1H), 8.77 (s, 1H), 8.36 (bs, 1H), 8.16-7.94 (m, 2H), 7.91 (d, J = 8.6 Hz, 1H), 7.53 (bs, 1H), 6.58 (t, J = 56.9 Hz, 1H), 5.87 (bs, 1H), 3.87 (s, 3H), 1.75-1.27 (m, 5H), 1.28 - 0.99 (m, 2H). Compound 117 (R)-(4-(5-(3-hydroxybicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 484.2 1H NMR (400 MHz, DMSO-d6) δ 9.93-9.63 (m, 2H), 8.85 (bs, 1H), 8.36 (bs, 1H), 8.18-7.92 (m, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.51 (bs, 1H), 6.42 (s, 1H), 5.87 (bs, 1H), 3.86 (s, 3H), 2.13 (s, 6H), 1.54 (bs, 3H). Compound 118 (R)-(4-(5-(3-hydroxy-3-methylbutyrylamino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 474.2 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.83 (bs, 1H), 8.75 (bs, 1H), 8.35 (bs, 1H), 8.17-792 (m, 2H), 7.88 (d, J = 8.6 Hz, 1H), 7.53 (bs, 1H), 5.86 (bs, 1H), 4.74 (s, 1H), 3.87 (s, 3H), 2.47 (s, 2H), 1.46 (bs, 3H), 1.26 (s, 6H). Compound 119 (R)-(4-(5-(1-(difluoromethyl)-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 542.1 1H NMR (400 MHz, methanol-d4) δ 8.95 (s, 1H), 8.32 (s, 1H), 8.15 (m, 2H), 7.95 (d, 1H), 7.50 (s, 1H), 6.33 (t, J = 55.9 Hz, 1H), 6.08 (d, 1H), 4.00 (s, 3H), 3.23 (m, 2H), 3.07 (m, 2H), 1.64 (s, 3H). Compound 120 (R)-(1-methyl-4-(5-(3-oxo-1-(trifluoromethyl)cyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 538.1 1H NMR (400 MHz, Methanol-d4) δ 9.13 - 8.71 (m, 1H), 8.32 (s, 2H), 8.24 - 7.70 (m, 2H), 7.62 - 7.33 (m, 1H), 6.08 (d, 1H), 3.96 (m, 5H), 3.68 - 3.46 (m, 1H), 3.08 - 2.61 (m, 2H), 1.87 - 1.40 (m, 3H). Compound 121 (R)-(4-(5-((1s,3S)-3-cyano-1-methylcyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 495.1 1H NMR (400 MHz, methanol-d4) δ 9.05 (s, 1H), 8.34 (s, 1H), 8.28 - 8.00 (m, 2H), 7.94 (d, 1H), 7.51 (s, 1H), 6.09 (d, 1H), 4.01 (s, 3H), 3.39 (m, 1H), 2.94 - 2.78 (m, 2H), 2.49 - 2.34 (m, 2H), 1.58 (m, 6H). Compound 122 (R)-(4-(5-((1r,3R)-3-cyano-1-methylcyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 495.1 1H NMR (400 MHz, methanol-d4) δ 8.97 (d, 1H), 8.34 (s, 1H), 8.27 - 7.99 (m, 2H), 7.93 (d, 1H), 7.51 (s, 1H), 6.08 (d, 1H), 4.01 (s, 3H), 3.28 - 3.16 (m, 1H), 3.13 - 2.96 (m, 2H), 2.49 - 2.21 (m, 2H), 1.67 (s, 6H). Compound 123 (R)-(4-(5-(3-cyano-3-fluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 499.0 1H NMR (400 MHz, methanol-d4) δ 8.91 (s, 1H), 8.32 (s, 1H), 8.23 - 7.75 (m, 3H), 7.49 (s, 1H), 6.08 (d, 1H), 4.90 - 4.65 (m, 2H), 4.00 (s, 3H), 2.83 - 2.65 (m, 1H), 1.93 - 1.80 (m, 2H), 1.55 (d, 3H). Compound 124 (R)-(4-(5-((R)-2-hydroxypropionamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 446.0 1H NMR (400 MHz, methanol-d4) δ 9.26 - 8.87 (m, 1H), 8.47 - 8.20 (m, 2H), 8.20 - 7.77 (m, 2H), 7.49 (s, 1H), 6.09 (m, 1H), 4.34 (m, 1H), 4.00 (s, 3H), 1.86 - 1.53 (m, 3H), 1.49 (d, 3H). Compound 125 (R)-(4-(5-((S)-2-hydroxypropionamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 446.0 1H NMR (400 MHz, Methanol-d4) δ 9.26 - 8.86 (m, 1H), 8.44 - 8.19 (m, 2H), 8.19 - 7.77 (m, 2H), 7.49 (s, 1H), 6.09 (q, 1H), 4.34 (q, 1H), 4.00 (s, 3H), 1.63 (s, 3H), 1.48 (d, 3H). Compound 126 (R)-(4-(5-(2-hydroxyacetamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 432.0 1H NMR (400 MHz, methanol-d4) δ 9.01 (s, 1H), 8.51 - 8.29 (m, 1H), 8.23 (dd, 1H), 8.18 - 7.80 (m, 2H), 7.48 (s, 1H), 6.09 (m, 1H), 4.20 (s, 2H), 4.00 (s, 3H), 1.62 (s, 3H). Compound 127 (R)-(4-(5-((1r 3R)-3-cyanocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 481.1 1H NMR (400 MHz, methanol-d4) δ 8.96 (d, 1H), 8.33 (s, 1H), 8.12 (m, 2H), 7.91 (d, 1H), 7.43 (d,1H), 6.08 (d, 1H), 3.99 (s, 3H), 3.45 (m, 2H), 2.85 - 2.48 (m, 4H), 1.62 (s, 3H). Compound 128 (R)-(4-(5-((1s,3S)-3-cyanocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 481.1 1H NMR (400 MHz, methanol-d4) δ 8.91 (s, 1H), 8.32 (s, 1H), 7.91-8.12 (m, 3H), 6.08 (d, 1H), 3.99 (s, 3H), 3.32 - 3.54 (m, 2H), 2.80 (m, 2H), 2.64 (m, 2H), 1.62 (s, 3H). Compound 129 (R)-(4-(5-(2-cyano-2-methylpropylamino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 469.1 1H NMR (400 MHz, methanol-d4) δ 8.98 (s, 1H), 8.33 (s, 1H), 8.22 (m, 1H), 7.97 (m, 2H), 7.48 (s, 1H), 6.09 (m, 1H), 4.01 (s, 3H), 1.75 (s, 6H), 1.61 (s, 3H). Compound 130 (R)-(4-(5-(2-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 467.1 1H NMR (400 MHz, methanol-d4) δ 8.99 (s, 1H), 8.44 - 8.26 (m, 1H), 8.23 - 7.85 (m, 3H), 7.47 (s, 1H), 6.08 (m, 1H), 4.00 (s, 3H), 2.49 (m, 1H), 2.14 (m, 1H), 1.79 - 1.44 (m, 5H). Compound 131 (R)-(4-(5-(1,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 492.1 1H NMR (400 MHz, methanol-d4) δ 8.96 (d, 1H), 8.45 - 8.20 (m, 2H), 8.20 - 7.85 (m, 2H), 7.51 (s, 1H), 6.09 (d, 1H), 5.18 - 4.96 (m, 1H), 4.00 (s, 3H), 3.24 - 3.05 (m, 2H), 2.93 - 2.59 (m, 2H), 1.61 (d, 3H). Compound 132 (R)-(4-(5-(1-cyano-3-fluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 499.1 1H NMR (400 MHz, methanol-d4) δ 9.11 - 8.82 (m, 1H), 8.34 (s, 1H), 8.23 - 8.09 (m, 2H), 7.99 (m, 1H), 7.70 - 7.31 (m, 1H), 6.09 (d, 1H), 5.34 (m, 1H), 4.00 (s, 3H), 3.20 - 2.82 (m, 4H), 1.64 (s, 3H). Compound 133 (R)-(4-(5-((1r,3R)-1-fluoro-3-hydroxycyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 490.0 1H NMR (400 MHz, methanol-d4) δ 9.07 (s, 1H), 8.50 - 8.23 (m, 2H), 8.22 - 7.83 (m, 2H), 7.51 (s, 1H), 6.09 (d, 1H), 4.62 (m, 1H), 4.00 (s, 3H), 2.90 - 2.56 (m, 4H), 1.65 (s, 3H). Compound 134 (R)-(4-(5-((1s,3S)-1-fluoro-3-hydroxycyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 490.0 1H NMR (400 MHz, methanol-d4) δ 9.03 (s, 1H), 8.46 - 8.20 (m, 2H), 8.20 - 7.85 (m, 2H), 7.51 (s, 1H), 6.09 (d, 1H), 4.23 (m, 1H), 4.00 (s, 3H), 3.04 (m, 2H), 2.59 - 2.34 (m, 2H), 1.64 (s, 3H). Compound 135 (R)-(4-(5-(1-cyano-3-hydroxycyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 497.1 1H NMR (400 MHz, Methanol-d4) δ 8.98 (s, 1H), 8.33 (s, 1H), 8.22 (m, 1H), 8.15 - 7.86 (m, 2H), 7.48 (s, 1H), 6.09 (m, 1H), 4.63 - 4.25 (m, 1H), 4.01 (s, 3H), 3.18 (m, 1H), 3.06 - 2.91 (m, 1H), 2.80 - 2.56 (m, 2H), 1.63 (s, 3H). Compound 136 (R)-(4-(5-(3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 540.1 1H NMR (400 MHz, methanol-d4) δ 9.03 (s, 1H), 8.33 (s, 1H), 8.19 (m, 1H), 8.13 - 7.85 (m, 2H), 7.49 (s, 1H), 6.09 (m, 1H), 4.01 (s, 3H), 3.09 (m, 1H), 2.84 - 2.68 (m, 2H), 2.65 - 2.47 (m, 2H), 1.63 (s, 3H). Compound 137 (R)-(4-(5-((1R,2S)-2-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 467.1 1H NMR (400 MHz, Methanol-d4) δ 9.24 - 8.84 (m, 1H), 8.33 (d, 1H), 8.25 - 7.99 (m, 2H), 7.94 (d, 1H), 7.50 (s, 1H), 6.20 - 5.97 (m, 1H), 4.09 - 3.87 (m, 3H), 2.40 (m, 1H), 2.18 (m, 1H), 1.80 - 1.43 (m, 5H). Compound 138 (R)-(4-(5-((1s,3S)-3-cyano-3-methoxycyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 511.1 1H NMR (400 MHz, methanol-d4) δ 9.00 (s, 1H), 8.33 (s, 1H), 8.17 (m, 2H), 7.92 (d, 1H), 7.48 (s, 1H), 6.08 (m, 1H), 4.00 (s, 3H), 3.41 (s, 3H), 3.29 - 3.15 (m, 1H), 2.93 - 2.79 (m, 2H), 2.66 (m, 2H), 1.63 (s, 3H). Compound 139 (R)-(4-(5-((1r,3R)-3-cyano-3-methoxycyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 511.1 1H NMR (400 MHz, Methanol-d4) δ 9.02 (s, 1H), 8.34 (s, 1H), 8.17 (m, 2H), 7.92 (m, 1H), 7.49 (s, 1H), 6.08 (m, 1H), 4.01 (s, 3H), 3.52 - 3.38 (m, 4H), 3.00 - 2.84 (m, 2H), 2.70 (m, 2H), 1.63 (s, 3H). Compound 140 (R)-(4-(5-((1s,3S)-3-cyano-3-hydroxycyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 497.1 1H NMR (400 MHz, methanol-d4) δ 8.97 (d, 1H), 8.47 - 8.28 (m, 1H), 8.19 (m, 2H), 8.10 (d, 1H), 7.92 (d, 1H), 7.48 (s, 1H), 6.08 (m, 1H), 4.00 (s, 3H), 3.19 (m, 1H), 2.94 - 2.80 (m, 2H), 2.65 (m, 2H), 1.63 (s, 3H). Compound 141 (R)-(4-(5-(1-cyano-3-oxocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 495.0 1H NMR (400 MHz, methanol-d4) δ 8.92 (s, 1H), 8.32 (s, 1H), 8.22 - 8.08 (m, 2H), 7.96 (d, 1H), 7.48 (s, 1H), 6.09 (m, 1H), 4.00 (s, 3H), 3.15 - 2.74 (m, 4H), 1.62 (s, 3H). Compound 142 (R)-(4-(5-(2-cyanocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 481.1 1H NMR (400 MHz, Methanol-d4) δ 9.17 - 8.85 (m, 1H), 8.45 - 8.28 (m, 1H), 8.20 (m, 1H), 8.13 - 7.84 (m, 2H), 7.48 (s, 1H), 6.08 (m, 1H), 4.00 (s, 3H), 3.65 (m, 2H), 2.50 - 2.23 (m, 4H), 1.59 (d, 3H). Compound 143 (R)-(4-(5-(2-cyanopropionamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 455.0 1H NMR (400 MHz, methanol-d4) δ 8.91 (d, 1H), 8.33 (s, 1H), 8.15 (m, 1H), 7.95 (d, 2H), 7.48 (s, 1H), 6.09 (m, 1H), 4.00 (s, 3H), 3.92 (m, 1H), 1.66 (m, 6H). Compound 144 (R)-(4-(5-(3,3-difluoro-1-methylcyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 506.1 1H NMR (400 MHz, methanol-d4) δ 9.07 (s, 1H), 8.46 - 8.20 (m, 2H), 7.95 (d, 2H), 7.48 (s, 1H), 6.09 (m, 1H), 4.01 (s, 3H), 3.25 - 3.05 (m, 2H), 2.68 - 2.46 (m, 2H), 1.64 (s, 6H). Compound 145 (R)-(4-(5-(1,3-dicyano-2,2-dimethylcyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 520.1 1H NMR (400 MHz, methanol-d4) δ 8.91 (s, 1H), 8.32 (s, 1H), 8.16 (m, 2H), 7.95 (m, 1H), 7.46 (s, 1H), 6.08 (m, 1H), 4.00 (s, 3H), 3.04 (d, 1H), 1.66 (m, 6H), 1.32 (d, 3H). Compound 146 (R)-(4-(5-(1-cyano-2,2-dimethylcyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 495.1 1H NMR (400 MHz, methanol-d4) δ 8.98 (s, 1H), 8.33 (s, 1H), 8.22 (m, 1H), 7.96 (m, 2H), 7.48 (s, 1H), 6.09 (m, 1H), 4.00 (s, 3H), 1.93 (d, 1H), 1.63 (s, 3H), 1.53 (s, 3H), 1.47 (d, 1H), 1.24 (d, 3H). Compound 147 (R)-(4-(5-(1-cyano-2-(trifluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 535.1 1H NMR (400 MHz, methanol-d4) δ 8.93 (s, 1H), 8.42 - 8.27 (m, 1H), 8.20 (m, 2H), 8.15 - 7.86 (m, 1H), 7.47 (s, 1H), 6.09 (m, 1H), 4.00 (s, 3H), 3.12 - 2.95 (m, 1H), 2.25 - 2.07 (m, 2H), 1.62 (s, 3H). Compound 148 (R)-(4-(5-(1-cyano-2-methylcyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 481.1 1H NMR (400 MHz, methanol-d4) δ 8.95 (s, 1H), 8.33 (d, 1H), 8.21 (dd, 1H), 7.94 (d, 2H), 7.48 (s, 1H), 6.09 (m, 1H), 4.00 (s, 3H), 2.16 - 2.02 (m, 1H), 1.98 (dd, J = 8.9, 4.6 Hz, 1H), 1.63 (s, 3H), 1.44 (m, 4H). Compound 149 (R)-(1-methyl-4-(5-(spiro[2.2]pentane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 468.1 1H NMR (400 MHz, methanol-d4) δ 9.10 (s, 1H), 8.34 (s, 1H), 8.30 - 8.00 (m, 2H), 7.93 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 6.09 (q, J = 6.6 Hz, 1H), 4.01 (s, 3H), 2.20 (dd, J = 7.4, 4.2 Hz, 1H), 1.83 - 1.40 (m, 5H), 1.10 - 0.86 (m, 4H). Compound 150 (R)-(1-methyl-4-(5-((S)-5-oxopyrrolidine-3-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 485.1 1H NMR (400 MHz, methanol-d4) δ 9.05 (s, 1H), 8.43 - 8.26 (m, 1H), 8.25 - 8.01 (m, 2H), 7.94 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 30.4 Hz, 1H), 6.08 (d, J = 7.1 Hz, 1H), 4.01 (s, 3H), 3.79 - 3.61 (m, 2H), 3.55 (tt, J = 8.9, 6.5 Hz, 1H), 2.78 - 2.60 (m, 2H), 1.84 - 1.39 (m, 3H). Compound 151 (R)-(1-methyl-4-(5-((S)-5-oxopyrrolidine-2-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 485.1 1H NMR (400 MHz, methanol-d4) δ 9.01 (s, 1H), 8.31 (d, J = 20.5 Hz, 1H), 8.26 - 8.01 (m, 2H), 7.94 (d, J = 8.7 Hz, 1H), 7.64 - 7.38 (m, 1H), 6.08 (d, J = 6.5 Hz, 1H), 4.41 (dd, J = 8.7, 4.6 Hz, 1H), 4.01 (s, 3H), 2.67 - 2.35 (m, 3H), 2.27 (d, J = 10.5 Hz, 1H), 1.55 (d, J = 73.8 Hz, 3H). Compound 152 (R)-(1-methyl-4-(5-((R)-5-oxopyrrolidine-2-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 485.1 1H NMR (400 MHz, methanol-d4) δ 8.98 (s, 1H), 8.40 - 8.25 (m, 1H), 8.23 - 8.01 (m, 2H), 7.93 (d, J = 8.8 Hz, 1H), 7.62 - 7.40 (m, 1H), 6.08 (d, J = 7.5 Hz, 1H), 4.41 (dd, J = 8.7, 4.6 Hz, 1H), 4.00 (s, 3H), 2.67 - 2.45 (m, 2H), 2.39 (ddd, J = 16.9, 9.7, 5.5 Hz, 1H), 2.31 - 2.19 (m, 1H), 1.82 - 1.43 (m, 3H). Compound 153 (R)-(4-(5-(1,3-dioxolane-2-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 474.1 1H NMR (400 MHz, methanol-d4) δ 9.04 (s, 1H), 8.43 - 8.18 (m, 2H), 8.07 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.48 (s, 1H), 6.09 (q, J = 6.6 Hz, 1H), 4.25 - 4.12 (m, 2H), 4.12 - 4.03 (m, 2H), 4.00 (s, 3H), 1.63 (s, 3H). Compound 154 (R)-(4-(5-((1r,3R)-3-hydroxycyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 472.1 1H NMR (400 MHz, methanol-d4) δ 9.02 (s, 1H), 8.33 (s, 1H), 8.18 (dd, J = 8.7, 2.5 Hz, 2H), 7.92 (d, J = 8.7 Hz, 1H), 7.48 (s, 1H), 6.09 (q, J = 6.6 Hz, 1H), 4.58 - 4.46 (m, 1H), 4.00 (s, 3H), 3.21 (ttd, J = 9.9, 3.8, 1.1 Hz, 1H), 2.70 - 2.52 (m, 2H), 2.28 (dtd, J = 12.9, 6.7, 3.0 Hz, 2H), 1.63 (s, 3H). Compound 155 (R)-(4-(5-((1s,3S)-3-hydroxycyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 472.1 1H NMR (400 MHz, methanol-d4) δ 9.02 (s, 1H), 8.44 - 8.28 (m, 1H), 8.25 - 8.06 (m, 2H), 7.99 - 7.87 (m, 1H), 7.48 (s, 1H), 6.09 (q, J = 6.6 Hz, 1H), 4.19 (tt, J = 8.3, 6.9 Hz, 1H), 4.00 (s, 3H), 2.77 (tt, J = 9.7, 7.4 Hz, 1H), 2.57 (dddd, J = 9.4, 7.2, 5.5, 2.8 Hz, 2H), 2.24 (dtt, J = 11.5, 8.2, 1.4 Hz, 2H), 1.63 (s, 3H). Compound 156 (R)-(4-(5-((1r,3R)-3-methoxycyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 486.1 1H NMR (400 MHz, methanol-d4) δ 9.04 (s, 1H), 8.34 (s, 1H), 8.18 (dd, J = 8.7, 2.4 Hz, 2H), 7.92 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 6.09 (d, J = 7.4 Hz, 1H), 4.26 - 4.10 (m, 1H), 4.01 (s, 3H), 3.29 (s, 3H), 3.24 (dddd, J = 9.7, 8.5, 4.3, 1.0 Hz, 1H), 2.65 - 2.53 (m, 2H), 2.30 (dtd, J = 13.0, 6.1, 4.2 Hz, 2H), 1.65 (s, 3H). Compound 157 (R)-(4-(5-((1s,3S)-3-methoxycyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 486.1 1H NMR (400 MHz, methanol-d4) δ 9.01 (s, 1H), 8.33 (s, 1H), 8.16 (dd, J = 8.7, 2.5 Hz, 2H), 7.92 (d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 6.09 (d, J = 6.8 Hz, 1H), 4.00 (s, 3H), 3.91 (tt, J = 8.1, 6.7 Hz, 1H), 3.28 (s, 3H), 2.85 (tt, J = 9.7, 7.7 Hz, 1H), 2.56 (dddd, J = 12.3, 7.5, 4.0, 1.3 Hz, 2H), 2.23 (dddq, J = 13.8, 7.7, 2.8 Hz, 2H). = 11.1, 9.4, 7.9, 1.6 Hz, 2H), 1.65 (s, 3H). Compound 158 (R)-(4-(5-((1R,5R)-3-oxabicyclo[3.1.0]hexane-6-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 484.1 1H NMR (400 MHz, methanol-d4) δ 8.99 (s, 1H), 8.34 (s, 1H), 8.15 (dd, J = 8.7, 2.5 Hz, 2H), 7.92 (d, J = 8.7 Hz, 1H), 7.50 (s, 1H), 6.09 (d, J = 7.4 Hz, 1H), 4.03 - 3.93 (m, 4H), 3.82 (dd, J = 8.6, 1.8 Hz, 2H), 2.31 - 2.23 (m, 2H), 1.76 (t, J = 3.2 Hz, 1H), 1.65 (s, 3H). Compound 159 (R)-(4-(5-(2-oxabicyclo[3.1.0]hexane-6-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 484.1 1H NMR (400 MHz, methanol-d4) δ 8.94 (s, 1H), 8.34 (s, 1H), 8.11 (dd, J = 8.7, 2.5 Hz, 2H), 7.91 (d, J = 8.7 Hz, 1H), 7.50 (s, 1H), 6.09 (d, J = 6.9 Hz, 1H), 4.24 (dd, J = 5.0, 2.7 Hz, 1H), 4.12 (td, J = 9.5, 3.0 Hz, 1H), 4.00 (s, 3H), 3.58 (td, J = 9.5, 7.7 Hz, 1H), 2.35 - 2.20 (m, 2H), 2.20 - 2.06 (m, 2H), 1.64 (s, 3H). Compound 160 (R)-(1-methyl-4-(5-(1-(3-methylisoxazol-5-yl)cyclopropane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 523.1 1H NMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 8.33 (s, 1H), 8.22 - 8.00 (m, 2H), 7.92 (d, J = 8.7 Hz, 1H), 7.50 (s, 1H), 6.37 (s, 1H), 6.08 (d, J = 7.0 Hz, 1H), 4.00 (s, 3H), 2.32 (s, 3H), 1.76 (q, J = 4.3 Hz, 2H), 1.58 (d, J = 48.4 Hz, 3H), 1.46 (q, J = 4.3 Hz, 2H). Compound 161 (R)-(4-(5-((1S,2R)-2-fluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 462.1 1H NMR (400 MHz, methanol-d4) δ 8.77 (s, 1H), 8.24 - 7.50 (m, 4H), 5.95 (d, J = 7.6 Hz, 1H), 3.99 (s, 3H), 2.29 (dddd, J = 17.3, 10.4, 6.6, 1.6 Hz, 1H), 1.90 - 1.24 (m, 5H). Compound 162 (R)-(4-(5-(3-cyanobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 495.2 1H NMR (400 MHz, methanol-d4) δ 8.83 (s, 1H), 8.22 - 7.58 (m, 4H), 5.94 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 2.64 (s, 6H), 1.61 (s, 3H). Compound 163 (R)-(4-(5-(3-fluorobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 488.2 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.23 - 7.46 (m, 4H), 5.94 (d, J = 6.2 Hz, 1H), 3.99 (s, 3H), 2.47 (d, J = 2.4 Hz, 6H), 1.62 (s, 3H). Compound 164 (R)-(4-(5-((S)-2,2-difluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 480.0 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.26 - 7.50 (m, 4H), 5.95 (d, J = 7.2 Hz, 1H), 4.00 (s, 3H), 2.75 (ddd, J = 13.1, 10.8, 7.7 Hz, 1H), 2.23 - 2.07 (m, 1H), 1.98 - 1.79 (m, 1H), 1.62 (s, 3H). Compound 165 (R)-(4-(5-(1-(difluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 494.1 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.81 (bs, 1H), 9.63 (s, 1H), 8.70 (s, 1H), 8.19 (bs, 1H), 8.08-7.94 (m, 2H), 7.91 (d, J = 8.6 Hz, 1H), 6.58 (t, J = 56.9 Hz, 1H), 5.79 (bs, 1H), 3.88 (s, 3H), 1.57 (bs, 3H), 1.42-1.30 (m, 2H), 1.25 - 1.08 (m, 2H). Compound 166 (R)-(4-(5-(1-(difluoromethyl)cyclopropane-1-carboxamido)pyridine-2-)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester 510.2 1H NMR (400 MHz, DMSO-d6) δ 9.86 (bs, 1H), 9.63 (s, 1H), 8.73 (bs, 1H), 8.42 (bs, 1H), 8.10 - 7.82 (m, 3H), 6.58 (t, J = 56.9 Hz, 1H), 5.83 (bs, 1H), 3.89 (s, 3H), 1.57 (bs, 3H), 1.43-1.35 (m, 2H), 1.27 - 1.03 (m, 2H). Compound 167 (R)-(4-(5-(3-cyanobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester 511.2 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.01 (s, 1H), 9.86 (bs, 1H), 8.78 (s, 1H), 8.42 (bs, 1H), 8.12 - 7.80 (m, 3H), 5.83 (bs, 1H), 3.89 (s, 3H), 2.58 (s, 6H), 1.56 (bs, 3H). Compound 168 (R)-(4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester 485.2 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.89 (bs, 1H), 8.73 (s, 1H), 8.43 (bs, 1H), 8.07 - 7.83 (m, 3H), 5.83 (bs, 1H), 3.89 (s, 3H), 1.76-1.67 (m, 4H), 1.57 (bs, 3H). Compound 169 (R)-(4-(5-((1S,2R)-2-fluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester 444.1 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.43 - 7.72 (m, 4H), 7.35 (s, 1H), 5.99 (q, J = 6.3 Hz, 1H), 3.98 (s, 3H), 2.29 (dddd, J = 17.3, 10.5, 6.6, 1.6 Hz, 1H), 1.80 - 1.46 (m, 4H), 1.40 (dq, J = 13.0, 6.5 Hz, 1H). Compound 170 (R)-(1-methyl-4-(5-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester 520.1 1H NMR (400 MHz, methanol-d4) δ 8.87 (s, 1H), 8.25 - 7.96 (m, 3H), 7.92 (dd, J = 8.6, 0.8 Hz, 1H), 7.36 (s, 1H), 6.10 - 5.66 (m, 1H), 3.98 (s, 3H), 2.39 (s, 6H), 1.62 (s, 3H). Compound 171 (R)-(4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester 476.1 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.82 (s, 1H), 8.28 - 8.00 (m, 3H), 7.90 (d, J = 8.4 Hz, 1H), 7.54 - 7.10 (m, 1H), 6.14 - 5.79 (m, 1H), 3.98 (s, 3H), 3.17 - 3.13 (m, 1H), 3.03 - 2.72 (m, 4H), 1.62 (s, 3H). Compound 172 (R)-(4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester 451.1 1H NMR (400 MHz, methanol-d4) δ 8.81 (s, 1H), 8.15 (s, 1H), 8.07 (dd, J = 8.6, 2.6 Hz, 1H), 7.93 (dd, J = 8.6, 0.8 Hz, 1H), 7.36 (s, 1H), 5.99 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 1.88 - 1.42 (m, 8H). Compound 173 (R)-(4-(5-(3-fluorobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester 470.1 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.86 (s, 1H), 8.24 - 8.02 (m, 3H), 7.91 (dd, J = 8.7, 0.8 Hz, 1H), 7.51 - 7.21 (m, 1H), 6.19 - 5.83 (m, 1H), 3.98 (s, 3H), 2.47 (d, J = 2.4 Hz, 6H), 1.80 - 1.44 (m, 3H). Compound 174 (R)-(4-(5-(3-cyanobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester 477.1 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.85 (s, 1H), 8.28 - 7.96 (m, 3H), 7.91 (dd, J = 8.7, 0.8 Hz, 1H), 7.35 (s, 1H), 6.14 - 5.82 (m, 1H), 3.98 (s, 3H), 2.64 (s, 6H), 1.62 (s, 3H). Compound 175 (R)-(4-(5-(3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(5-fluoro-2-methylpyridin-3-yl)ethyl ester 490.1 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.78 (s, 1H), 8.25 (s, 1H), 8.10 (dd, J = 8.6, 2.6 Hz, 1H), 7.89 (dd, J = 8.7, 0.8 Hz, 1H), 7.84 - 7.40 (m, 1H), 6.14 - 5.72 (m, 1H), 3.98 (s, 3H), 3.22 - 3.08 (m, 1H), 3.07 - 2.71 (m, 4H), 2.56 (s, 3H), 1.80 - 1.39 (m, 3H). Compound 176 (R)-(4-(5-((1S,2R)-2-fluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(5-fluoro-2-methylpyridin-3-yl)ethyl ester 458.2 1H NMR (400 MHz, methanol-d4) δ 8.75 (s, 1H), 8.36 - 7.24 (m, 4H), 5.98 (d, J = 6.7 Hz, 1H), 3.97 (s, 3H), 2.56 (s, 3H), 2.29 (dddd, J = 17.3, 10.5, 6.6, 1.6 Hz, 1H), 1.81 - 1.34 (m, 5H). Compound 177 (R)-(4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(5-fluoro-2-methylpyridin-3-yl)ethyl ester 465.1 1H NMR (400 MHz, methanol-d4) δ 8.77 (s, 1H), 8.27 (s, 1H), 8.07 (dd, J = 8.6, 2.6 Hz, 1H), 7.92 (dd, J = 8.6, 0.8 Hz, 1H), 7.71 (s, 1H), 6.18 - 5.80 (m, 1H), 3.98 (s, 3H), 2.56 (s, 3H), 1.81 - 1.67 (m, 4H), 1.59 (s, 3H). Compound 178 (R)-(4-(5-(3-cyanobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(5-fluoro-2-methylpyridin-3-yl)ethyl ester 491.1 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.81 (s, 1H), 8.26 (s, 1H), 8.09 (dd, J = 8.7, 2.6 Hz, 1H), 7.90 (dd, J = 8.6, 0.8 Hz, 1H), 7.86 - 7.51 (m, 1H), 6.10 - 5.87 (m, 1H), 3.98 (s, 3H), 2.64 (s, 6H), 2.56 (s, 3H), 1.59 (s, 3H). Compound 179 (R)-(4-(5-(3-fluorobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(5-fluoro-2-methylpyridin-3-yl)ethyl ester 484.1 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.82 (s, 1H), 8.26 (s, 1H), 8.10 (dd, J = 8.7, 2.6 Hz, 1H), 7.90 (dd, J = 8.6, 0.8 Hz, 1H), 7.86 - 7.53 (m, 1H), 6.11 - 5.81 (m, 1H), 3.98 (s, 3H), 2.56 (s, 3H), 2.47 (d, J = 2.4 Hz, 6H), 1.59 (s, 3H). Compound 180 (R)-(4-(5-((S)-2,2-difluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(5-fluoro-2-methylpyridin-3-yl)ethyl ester 476.1 1H NMR (400 MHz, methanol-d4) δ 8.77 (s, 1H), 8.26 (s, 1H), 8.10 (dd, J = 8.7, 2.6 Hz, 1H), 7.91 (dd, J = 8.6, 0.8 Hz, 1H), 7.86 - 7.49 (m, 1H), 6.09 - 5.82 (m, 1H), 3.98 (s, 3H), 2.75 (ddd, J = 13.2, 10.8, 7.8 Hz, 1H), 2.56 (s, 3H), 2.23 - 2.07 (m, 1H), 1.95 - 1.80 (m, 1H), 1.59 (s, 3H). Compound 181 1-(2-chloro-6-fluoropyridin-3-yl)ethyl (4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate 485.0 1H NMR (400 MHz, methanol-d4) δ 8.93 (s, 1H), 8.19 (dd, J = 8.7, 2.5 Hz, 2H), 7.97 (d, J = 8.7 Hz, 1H), 7.17 (s, 1H), 6.08 (d, J = 6.8 Hz, 1H), 4.00 (s, 3H), 1.86 - 1.75 (m, 2H), 1.75 - 1.67 (m, 2H), 1.63 (s, 3H). Compound 182 1-(2-chloro-6-fluoropyridin-3-yl)ethyl (4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate 434.0 1H NMR (400 MHz, methanol-d4) δ 9.00 (s, 1H), 8.15 (dd, J = 8.7, 2.5 Hz, 2H), 7.94 (d, J = 8.7 Hz, 1H), 7.17 (s, 1H), 6.08 (q, J = 6.6 Hz, 1H), 4.00 (s, 3H), 2.22 (s, 3H), 1.63 (s, 3H). Compound 183 (R)-(4-(5-(1-cyanocyclopropane-1-carboxamido)-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 485.1 1H NMR (400 MHz, methanol-d4) δ 8.83 (d, J = 9.7 Hz, 1H), 8.32 (d, J = 4.7 Hz, 1H), 8.04 (s, 1H), 7.84 (d, J = 11.1 Hz, 1H), 7.47 (s, 1H), 6.16 - 5.98 (m, 1H), 3.99 (s, 3H), 1.86 - 1.69 (m, 4H), 1.61 (s, 3H). Compound 184 (R)-(4-(5-(3-cyanobicyclo[1.1.1]pentane-1-carboxamido)-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 511.1 1H NMR (400 MHz, methanol-d4) δ 8.84 (d, J = 9.7 Hz, 1H), 8.32 (d, J = 4.9 Hz, 1H), 8.06 (s, 1H), 7.82 (d, J = 11.3 Hz, 1H), 7.47 (s, 1H), 6.21 - 5.89 (m, 1H), 3.99 (s, 3H), 2.66 (s, 6H), 1.61 (s, 3H). Compound 195 (R)-(1-methyl-4-(5-((R)-5-oxopyrrolidine-3-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 485.1 1H NMR (400 MHz, methanol-d4) δ 9.02 (s, 1H), 8.34 (s, 1H), 8.25 - 8.01 (m, 2H), 7.93 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 6.08 (d, J = 6.8 Hz, 1H), 4.01 (s, 3H), 3.78 - 3.62 (m, 2H), 3.54 (tt, J = 8.9, 6.6 Hz, 1H), 2.79 - 2.60 (m, 2H), 1.65 (s, 3H). Compound 196 (R)-(4-(5-(2-(1,3-dioxopentan-2-yl)acetamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 488.1 1H NMR (400 MHz, methanol-d4) δ 9.02 (s, 1H), 8.34 (s, 1H), 8.18 (dd, J = 8.8, 2.5 Hz, 1H), 8.10 (s, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 6.09 (q, J = 6.6 Hz, 1H), 5.32 (t, J = 5.0 Hz, 1H), 4.07 - 4.02 (m, 2H), 4.01 (s, 3H), 3.95 - 3.89 (m, 2H), 2.80 (d, J = 5.0 Hz, 2H), 1.65 (s, 3H). Compound 197 (R)-(1-methyl-4-(5-((1R,2R)-2-phenylcyclopropane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 518.2 1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.43 - 7.77 (m, 4H), 7.65 - 7.05 (m, 6H), 6.08 (d, J = 6.8 Hz, 1H), 3.98 (s, 3H), 2.54 (dddd, J = 8.8, 6.3, 4.1, 2.0 Hz, 1H), 2.10 (ddd, J = 8.2, 5.3, 4.1 Hz, 1H), 1.80 - 1.33 (m, 5H). Compound 198 (R)-(4-(5-(3,3-difluoro-1-(pyridin-3-yl)cyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 569.2 1H NMR (400 MHz, methanol-d4) δ 9.00 (s, 1H), 8.95 - 8.49 (m, 2H), 8.45 - 7.71 (m, 5H), 7.50 (s, 1H), 6.05 (s, 1H), 3.99 (s, 3H), 3.71 (m, 2H), 3.44 - 3.35 (m, 2H), 1.63 (s, 3H). Compound 199 (R)-(4-(5-(2,2-difluorospiro[2.2]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 504.1 1H NMR (400 MHz, methanol-d4) δ 9.01 (s, 1H), 8.33 (s, 1H), 8.17 (ddd, J = 8.8, 4.3, 2.4 Hz, 2H), 7.94 (d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 6.09 (d, J = 6.8 Hz, 1H), 4.01 (s, 3H), 2.98 - 2.90 (m, 1H), 1.65 (s, 3H), 1.51 (d, J = 6.4 Hz, 1H), 1.48 - 1.39 (m, 1H), 1.33 (dq, J = 23.5, 7.6, 6.2 Hz, 2H). Compound 200 (R)-(4-(5-(3,3-difluoro-1-(hydroxymethyl)cyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 522.2 1H NMR (400 MHz, methanol-d4) δ 9.08 (s, 1H), 8.49 - 8.21 (m, 2H), 8.01 (m, 2H), 7.50 (s, 1H), 6.16 - 5.97 (m, 1H), 3.97 (m, 5H), 3.08 (m, 2H), 2.70 (m, 2H), 1.63 (s, 3H). Compound 201 (R)-(4-(5-((1R,2R)-1-cyano-2-(trifluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 535.1 1H NMR (400 MHz, methanol-d4) δ 8.88 - 8.76 (m, 1H), 8.40 - 8.26 (m, 1H), 8.05 (m, 2H), 7.91 (m, 1H), 7.48 (s, 1H), 6.07 (m, 1H), 3.98 (s, 3H), 3.10 - 2.91 (m, 1H), 2.27 - 2.08 (m, 2H), 1.62 (s, 3H). Compound 202 (R)-(4-(5-((1S,2S)-1-cyano-2-(trifluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 535.1 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.39 - 8.22 (m, 1H), 8.05 (m, 2H), 7.92 (m, 1H), 7.46 (m, 1H), 6.07 (m, 1H), 3.98 (s, 3H), 3.12 - 2.95 (m, 1H), 2.24 - 2.07 (m, 2H), 1.63 (s, 3H). Compound 203 (R)-(4-(5-((R)-2-cyanopropionamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 455.1 1H NMR (400 MHz, methanol-d4) δ 9.05 - 8.72 (m, 1H), 8.44 - 8.23 (m, 1H), 8.19 - 7.79 (m, 3H), 7.44 (m, 1H), 6.07 (m, 1H), 3.99 (s, 3H), 3.92 (m, 1H), m 1.81 - 1.48 (m, 6H). Compound 204 (R)-(4-(5-((S)-2-cyanopropionamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 455.1 1H NMR (400 MHz, methanol-d4) δ 8.83 (s, 1H), 8.39 - 8.22 (m, 1H), 8.04 (m, 2H), 7.92 (m, 1H), 7.43 (m, 1H), 6.07 (m, 1H), 3.98 (s, 3H), 3.95 - 3.82 (m, 1H), 1.73 - 1.48 (m, 6H). Compound 205 (R)-(1-methyl-4-(5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 547.9 1H NMR (400 MHz, methanol-d4) δ 9.48 (s, 2H), 9.00 (s, 1H), 8.30 (s, 1H), 8.21 (dd, J = 8.7, 2.6 Hz, 1H), 8.15 - 7.88 (m, 2H), 7.47 (s, 1H), 6.07 (d, J = 6.7 Hz, 1H), 3.98 (s, 3H), 1.60 (s, 3H). Compound 206 (R)-(4-(5-(2-(difluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 530.0 1H NMR (400 MHz, methanol-d4) δ 9.43 (s, 2H), 9.00 (s, 1H), 8.30 (s, 1H), 8.21 (dd, J = 8.6, 2.6 Hz, 1H), 8.15 - 7.84 (m, 2H), 7.47 (s, 1H), 6.84 (t, J = 54.2 Hz, 1H), 6.07 (d, J = 6.8 Hz, 1H), 3.98 (s, 3H), 1.60 (s, 3H). Compound 207 (R)-(1-methyl-4-(5-((1RS,2RS)-2-methylcyclopropane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 458.1 1H NMR (400 MHz, methanol-d4) δ 8.78 (s, 1H), 8.27 - 7.50 (m, 4H), 5.95 (d, J = 7.6 Hz, 1H), 3.99 (s, 3H), 1.82 - 1.31 (m, 5H), 1.26 - 1.15 (m, 4H), 0.76 (ddd, J = 8.0, 6.3, 3.9 Hz, 1H). Compound 208 (R)-(4-(5-((1RS,2RS)-2-(fluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 476.1 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.23 - 7.52 (m, 4H), 5.95 (d, J = 7.3 Hz, 1H), 4.53 (ddd, J = 48.7, 10.0, 5.8 Hz, 1H), 4.38 - 4.09 (m, 1H), 3.99 (s, 3H), 1.92 - 1.79 (m, 2H), 1.62 (s, 3H), 1.31 (dq, J = 8.3, 3.8 Hz, 1H), 1.01 (dt, J = 10.8, 5.5 Hz, 1H). Compound 209 (R)-(1-methyl-4-(5-((1RS,2RS)-2-(trifluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 512.1 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.34 - 7.48 (m, 4H), 5.95 (d, J = 5.6 Hz, 1H), 3.99 (s, 3H), 2.38 - 2.13 (m, 2H), 1.85 - 1.18 (m, 5H). Compound 210 (R)-(4-(5-((1RS,2RS)-2-methoxycyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 474.2 1H NMR (400 MHz, methanol-d4) δ 8.77 (s, 1H), 8.32 - 7.55 (m, 4H), 5.95 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 3.61 (ddt, J = 6.1, 3.9, 1.8 Hz, 1H), 3.44 (d, J = 1.2 Hz, 3H), 1.96 (ddd, J = 9.5, 5.8, 2.0 Hz, 1H), 1.62 (s, 3H), 1.38 - 1.19 (m, 2H). Compound 211 (R)-(1-methyl-4-(5-((1RS,2RS)-2-nitrocyclopropane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 489.1 1H NMR (400 MHz, methanol-d4) δ 8.78 (s, 1H), 8.34 - 7.55 (m, 4H), 5.94 (d, J = 6.7 Hz, 1H), 4.77 - 4.63 (m, 1H), 3.99 (s, 3H), 2.96 (ddd, J = 10.0, 7.1, 2.7 Hz, 1H), 2.17 - 2.02 (m, 1H), 1.84 (tdd, J = 7.1, 5.7, 1.1 Hz, 1H), 1.61 (s, 3H). Compound 212 (R)-(4-(5-(6-chloronicotinamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 515.0 1H NMR (400 MHz, methanol-d4) δ 9.03 - 8.85 (m, 2H), 8.35 (dd, J = 8.3, 2.5 Hz, 1H), 8.23 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 (s, 1H), 7.99 - 7.72 (m, 2H), 7.64 (dd, J = 8.3, 0.7 Hz, 1H), 5.94 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 1.60 (s, 3H). Compound 213 (R)-(4-(5-(2-fluoroisocyanamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 499.1 1H NMR (400 MHz, methanol-d4) δ 8.95 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.24 (dd, J = 8.7, 2.6 Hz, 1H), 8.02 (s, 1H), 7.97 (dd, J = 8.6, 0.7 Hz, 1H), 7.94 - 7.68 (m, 2H), 7.59 (d, J = 1.8 Hz, 1H), 5.94 (d, J = 6.7 Hz, 1H), 3.99 (s, 3H), 1.60 (s, 3H). Compound 214 (R)-(4-(5-(3-(difluoromethyl)oxy-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 510.2 1H NMR (400 MHz, methanol-d4) δ 8.83 (s, 1H), 8.28 - 7.35 (m, 4H), 6.43 (t, J = 55.6 Hz, 1H), 5.95 (d, J = 6.8 Hz, 1H), 5.03 (dt, J = 7.0, 1.8 Hz, 2H), 4.85 (d, J = 7.0 Hz, 2H), 4.00 (s, 3H), 1.62 (s, 3H). Compound 215 (R)-(1-methyl-4-(5-(3-(methylsulfonyl)bicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 548.1 1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.22 - 7.49 (m, 4H), 5.95 (d, J = 7.2 Hz, 1H), 4.00 (s, 3H), 2.99 (s, 3H), 2.58 (s, 6H), 1.62 (s, 3H). Compound 216 (R)-(4-(5-((1RS,2RS)-2-(difluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 519.1 1H NMR (400 MHz, methanol-d4) δ 8.86 (s, 1H), 8.16 (m, 1H), 8.12 - 7.72 (m, H), 6.20 -5.96 (m, 2H), 4.01 (s, 3H), 2.61 (m, 1H), 2.13 - 1.96 (m, 2H), 1.65 (s, 3H). Compound 217 (R)-(1-methyl-4-(5-((1RS,2RS)-2-(pyridin-4-yl)cyclopropane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 521.1 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.47 - 8.36 (m, 2H), 8.16 - 7.77 (m, 4H), 7.31 - 7.23 (m, 2H), 5.95 (d, J = 7.3 Hz, 1H), 3.99 (s, 3H), 2.56 (ddd, J = 9.1, 6.3, 4.0 Hz, 1H), 2.25 (ddd, J = 8.5, 5.5, 4.0 Hz, 1H), 1.83 - 1.35 (m, 5H). Compound 218 (R)-(4-(5-((1S,2R)-2-chlorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 478.2 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.24 - 7.51 (m, 4H), 5.95 (d, J = 7.4 Hz, 1H), 3.99 (s, 3H), 2.36 (ddd, J = 8.6, 5.7, 3.7 Hz, 1H), 2.18 - 2.07 (m, 1H), 1.89 - 1.33 (m, 5H). Compound 219 (R)-(4-(5-(5-(difluoromethyl)nicotinamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 531.1 1H NMR (400 MHz, methanol-d4) δ 9.34 - 9.18 (m, 1H), 9.01 - 8.90 (m, 2H), 8.58 (s, 1H), 8.26 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 (s, 1H), 8.00 - 7.75 (m, 2H), 7.05 (t, J = 55.3 Hz, 1H), 5.95 (d, J = 7.3 Hz, 1H), 3.99 (s, 3H), 1.60 (s, 3H). Compound 220 (R)-(4-(5-(6-fluoronicotinoylamino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 499.1 1H NMR (400 MHz, methanol-d4) δ 8.94 (s, 1H), 8.83 (d, J = 2.5 Hz, 1H), 8.50 (ddd, J = 8.6, 7.5, 2.6 Hz, 1H), 8.23 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 (s, 1H), 7.98 - 7.67 (m, 2H), 7.24 (dd, J = 8.6, 2.5 Hz, 1H), 5.94 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 221 (R)-(1-methyl-4-(5-(6-methylnicotinamide)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 495.1 1H NMR (400 MHz, methanol-d4) δ 9.01 (d, J = 2.4 Hz, 1H), 8.94 (s, 1H), 8.29 (dd, J = 8.2, 2.4 Hz, 1H), 8.23 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 (s, 1H), 7.99 - 7.66 (m, 2H), 7.48 (d, J = 8.2 Hz, 1H), 5.94 (d, J = 6.5 Hz, 1H), 3.99 (s, 3H), 2.64 (s, 3H), 1.61 (s, 3H). Compound 222 (R)-(4-(5-(6-(difluoromethyl)nicotinamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 531.1 1H NMR (400 MHz, methanol-d4) δ 9.19 (s, 1H), 8.96 (s, 1H), 8.52 (dd, J = 8.1, 2.2 Hz, 1H), 8.25 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.90 - 7.61 (m, 2H), 6.82 (t, J = 55.0 Hz, 1H), 5.94 (d, J = 7.3 Hz, 1H), 3.99 (s, 3H), 1.60 (s, 3H). Compound 223 (R)-(4-(5-(2-methoxyisocyanamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 511.1 1H NMR (400 MHz, methanol-d4) δ 8.94 (s, 1H), 8.32 (dd, J = 5.3, 0.8 Hz, 1H), 8.22 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 (s, 1H), 8.00 - 7.71 (m, 2H), 7.43 (dd, J = 5.3, 1.5 Hz, 1H), 7.31 (dd, J = 1.5, 0.8 Hz, 1H), 5.94 (d, J = 7.0 Hz, 1H), 4.06 - 3.92 (m, 6H), 1.60 (s, 3H). Compound 224 (R)-(4-(5-(2-(difluoromethyl)isoxanthamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 531.1 1H NMR (400 MHz, methanol-d4) δ 8.97 (s, 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.32 - 8.19 (m, 2H), 8.10 - 8.01 (m, 2H), 8.00 - 7.75 (m, 2H), 6.85 (t, J = 55.1 Hz, 1H), 5.94 (d, J = 6.4 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 225 (R)-(1-methyl-4-(5-(2-(trifluoromethyl)isoxanthamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 549.1 1H NMR (400 MHz, methanol-d4) δ 9.10 - 8.85 (m, 2H), 8.35 (t, J = 1.2 Hz, 1H), 8.26 (dd, J = 8.6, 2.6 Hz, 1H), 8.16 (dd, J = 5.0, 1.6 Hz, 1H), 8.02 (s, 1H), 8.01 - 7.66 (m, 2H), 5.94 (d, J = 6.4 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 226 (R)-(4-(5-(3,3-difluoro-1-methylcyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 508.0 1H NMR (400 MHz, methanol-d4) δ 9.04 (s, 1H), 8.42 - 8.18 (m, 1H), 8.06 (s, 1H), 7.96 (m, 2H), 5.96 (m, 1H), 4.02 (s, 3H), 3.27 - 2.96 (m, 2H), 2.70 - 2.41 (m, 2H), 1.64 (s, 6H). Compound 227 (R)-(1-methyl-4-(5-(4-methylisoxazole-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 485.1 1H NMR (400 MHz, DMSO-d6) δ 10.98 (bs, 1H), 9.82 (bs, 1H), 8.89 (bs, 1H), 8.75 (s, 1H), 8.29-7.25 (m, 4H), 5.80 (bs, 1H), 3.89 (s, 3H), 2.32 (s, 3H), 1.40 (bs, 3H). Compound 228 (R)-(1-methyl-4-(5-(3-methyl-1,1-dioxothiocyclobutane-3-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 522.1 1H NMR (400 MHz, methanol-d4) δ 8.81 (s, 1H), 8.23 - 7.60 (m, 4H), 5.95 (d, J = 7.0 Hz, 1H), 4.80 - 4.68 (m, 2H), 4.14 - 3.91 (m, 5H), 1.86 (s, 3H), 1.62 (s, 3H). Compound 229 (R)-(4-(5-((1RS,5SR,6SR)-3,3-dioxo-3-thiobicyclo[3.1.0]hexane-6-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 534.1 1H NMR (400 MHz, methanol-d4) δ 8.77 (s, 1H), 8.27 - 7.62 (m, 4H), 5.95 (d, J = 6.4 Hz, 1H), 4.00 (s, 3H), 3.61 - 3.44 (m, 2H), 2.46 - 2.31 (m, 2H), 2.29 - 2.18 (m, 1H), 1.62 (s, 3H). Compound 230 (R)-(4-(5-((1RS,5SR,6SR)-3,3-difluorobicyclo[3.1.0]hexane-6-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 520.2 1H NMR (400 MHz, methanol-d4) δ 8.77 (s, 1H), 8.18 - 7.59 (m, 4H), 6.09 - 5.77 (m, 1H), 3.99 (s, 3H), 2.55 (dtd, J = 23.8, 14.4, 3.1 Hz, 2H), 2.31 (dd, J = 19.4, 14.9 Hz, 2H), 2.13 - 1.99 (m, 2H), 1.85 (q, J = 3.0 Hz, 1H), 1.61 (s, 3H). Compound 231 (R)-(1-methyl-4-(5-(6-methylpyridin-4-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 496.1 1H NMR (400 MHz, methanol-d4) δ 9.49 (d, J = 2.1 Hz, 1H), 8.96 (s, 1H), 8.25 (dd, J = 8.6, 2.6 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 8.02 - 7.70 (m, 2H), 5.94 (d, J = 6.7 Hz, 1H), 3.99 (s, 3H), 2.83 (s, 3H), 1.61 (s, 3H). Compound 232 (R)-(4-(5-(2-aminoisocyanamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 496.1 1H NMR (400 MHz, methanol-d4) δ 8.93 (s, 1H), 8.21 (dd, J = 8.6, 2.6 Hz, 1H), 8.09 - 8.05 (m, 1H), 8.03 (s, 1H), 7.99 - 7.76 (m, 2H), 7.10 - 6.96 (m, 2H), 5.94 (d, J = 7.1 Hz, 1H), 3.99 (s, 2H), 1.61 (s, 3H). Compound 233 (R)-(1-methyl-4-(5-(pyrimidine-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 482.1 1H NMR (400 MHz, methanol-d4) δ 9.39 - 9.23 (m, 3H), 8.95 (s, 1H), 8.25 (dd, J = 8.7, 2.6 Hz, 1H), 8.03 (s, 1H), 8.00 - 7.91 (m, 2H), 5.95 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 234 (R)-(1-methyl-4-(5-(2-methylpyrimidine-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 496.1 1H NMR (400 MHz, methanol-d4) δ 9.21 (s, 2H), 8.94 (s, 1H), 8.23 (dd, J = 8.7, 2.6 Hz, 1H), 8.03 (s, 1H), 8.00 - 7.91 (m, 2H), 5.94 (d, J = 7.5 Hz, 1H), 3.99 (s, 3H), 2.79 (s, 3H), 1.61 (s, 3H). Compound 235 (R)-(4-(5-(2-cyanopyrimidine-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 507.1 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.87 (s, 1H), 9.48 (s, 2H), 8.88 (s, 1H), 8.21 (dd, J = 8.6, 2.6 Hz, 2H), 8.07 - 7.86 (m, 2H), 5.81 (s, 1H), 3.90 (s, 3H), 1.55 (s, 3H). Compound 236 (R)-(1-methyl-4-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 511.1 1H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.50 (d, J = 2.6 Hz, 1H), 8.17 (dd, J = 8.6, 2.6 Hz, 1H), 8.07 (dd, J = 9.5, 2.7 Hz, 1H), 8.02 (s, 1H), 7.97 - 7.73 (m, 2H), 6.61 (d, J = 9.5 Hz, 1H), 5.94 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 3.66 (s, 3H), 1.61 (s, 3H). Compound 237 (R)-(4-(5-((1RS,2RS)-2-(6-fluoropyridin-3-yl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 539.0 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.21 - 7.66 (m, 6H), 7.04 (dd, J = 8.5, 2.6 Hz, 1H), 5.94 (d, J = 6.9 Hz, 1H), 3.99 (s, 3H), 2.60 (dt, J = 10.1, 5.4 Hz, 1H), 2.14 (ddd, J = 8.3, 5.2, 4.1 Hz, 1H), 1.84 - 1.34 (m, 5H). Compound 238 (R)-(4-(5-((1RS,2RS)-2-(3-chloropyridin-4-yl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 555.0 1H NMR (400 MHz, methanol-d4) δ 8.80 (s, 1H), 8.55 (s, 1H), 8.42 (d, J = 5.1 Hz, 1H), 8.25 - 7.51 (m, 4H), 7.20 (d, J = 5.2 Hz, 1H), 5.95 (d, J = 6.3 Hz, 1H), 4.00 (s, 3H), 2.84 (dddd, J = 8.6, 6.3, 4.4, 1.5 Hz, 1H), 2.24 - 2.10 (m, 1H), 1.90 - 1.31 (m, 5H). Compound 239 (R)-(1-methyl-4-(5-(4-methyl-1,2,5-dioxadiazole-3-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 486.0 1H NMR (400 MHz, DMSO-d6) δ 11.33 (bs, 1H), 9.82 (bs, 1H), 8.88 (s, 1H), 8.29-8.10 (m, 2H), 8.10 - 7.74 (m, 2H), 5.80 (bs, 1H), 3.90 (s, 3H), 2.58 (s, 3H), 1.56 (bs, 3H). Compound 240 (R)-(4-(5-((1r,3R)-3-cyano-1-methylcyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 497.1 1H NMR (400 MHz, Methanol-d4) δ 9.03 (s, 1H), 8.27 (m, 1H), 8.13 - 7.74 (m, 3H), 5.95 (m, 1H), 4.01 (s, 3H), 3.28 - 3.13 (m, 1H), 3.11 - 2.98 (m, 2H), 2.35 (m, 2H), 1.66 (s, 6H). Compound 241 (R)-(4-(5-(2,5-difluoropyridin-3-yl)ethyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate 517.0 1H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.31 (dd, J = 3.1, 1.7 Hz, 1H), 8.25 - 8.10 (m, 2H), 8.03 (s, 1H), 8.01 - 7.93 (m, 2H), 5.94 (d, J = 6.7 Hz, 1H), 3.99 (s, 3H), 1.60 (s, 3H). Compound 242 (R)-(1-methyl-4-(5-(6-(trifluoromethyl)nicotinamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 549.0 1H NMR (400 MHz, methanol-d4) δ 9.25 (d, J = 2.1 Hz, 1H), 9.06 - 8.84 (m, 1H), 8.56 (dd, J = 8.2, 2.1 Hz, 1H), 8.23 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.98 - 7.72 (m, 2H), 5.95 (d, J = 7.3 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 243 (R)-(4-(5-(2,3-difluoroisocyanamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 516.9 1H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.21 (dd, J = 8.6, 2.6 Hz, 1H), 8.14 (dd, J = 5.0, 1.4 Hz, 1H), 8.08 - 7.69 (m, 3H), 7.61 (dd, J = 5.0, 4.1 Hz, 1H), 5.94 (d, J = 6.9 Hz, 1H), 3.99 (s, 3H), 1.60 (s, 3H). Compound 244 (R)-(4-(5-(2,6-difluoroisocyanamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 516.9 1H NMR (400 MHz, methanol-d4) δ 8.94 (s, 1H), 8.23 (dd, J = 8.7, 2.6 Hz, 1H), 8.12 - 7.67 (m, 3H), 7.52 (s, 2H), 5.94 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 1.60 (s, 3H). Compound 245 (R)-(4-(5-((1R,2R)-1-cyano-2-(difluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 519.1 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.16 - 7.99 (m, 2H), 7.93 (m, 2H), 6.20-5.93 (m, 2H), 3.99 (s, 3H), 2.66 - 2.48 (m, 1H), 2.10 - 1.90 (m, 2H), 1.61 (s, 3H). Compound 246 (R)-(4-(5-((1S,2S)-1-cyano-2-(difluoromethyl)cyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 519.1 1H NMR (400 MHz, methanol-d4) δ 8.80 (s, 1H), 8.15 - 7.99 (m, 2H), 7.98 - 7.83 (m, 2H), 6.20-5.94 (m, 2H), 3.99 (s, 3H), 2.59 (m, 1H), 2.10 - 1.92 (m, 2H), 1.61 (s, 3H). Compound 247 (R)-(4-(5-((1RS,3RS)-2,2-difluoro-3-phenylcyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 556.0 1H NMR (400 MHz, methanol-d4) δ 8.82 (s, 1H), 8.31 - 7.66 (m, 4H), 7.49 - 7.24 (m, 5H), 5.95 (d, J = 7.5 Hz, 1H), 4.00 (s, 3H), 3.65 (ddd, J = 11.7, 7.8, 5.1 Hz, 1H), 3.09 (ddd, J = 11.2, 7.9, 3.0 Hz, 1H), 1.62 (s, 3H). Compound 248 (R)-(4-(5-((1RS,2SR)-3,3-difluoro-[1,1'-bis(cyclopropane)]-2-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 520.0 1H NMR (400 MHz, methanol-d4) δ 8.76 (s, 1H), 8.26 - 7.59 (m, 4H), 5.94 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 2.44 (dd, J = 13.2, 7.4 Hz, 1H), 2.26 (dtd, J = 13.6, 7.0, 3.6 Hz, 1H), 1.61 (s, 3H), 1.07 - 0.82 (m, 1H), 0.81 - 0.53 (m, 2H), 0.53 - 0.24 (m, 2H). Compound 249 (R)-(1-methyl-4-(5-(2-methylpyrimidine-4-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 496.0 1H NMR (400 MHz, methanol-d4) δ 9.05 (s, 1H), 8.97 (d, J = 5.1 Hz, 1H), 8.35 (dd, J = 8.6, 2.6 Hz, 1H), 8.10 - 7.70 (m, 4H), 5.95 (d, J = 6.5 Hz, 1H), 3.99 (s, 3H), 2.86 (s, 3H), 1.61 (s, 3H). Compound 250 (R)-(4-(5-(6-chloropyridin-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 516.0 1H NMR (400 MHz, methanol-d4) δ 9.06 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.35 (dd, J = 8.7, 2.6 Hz, 1H), 8.04 (t, J = 6.6 Hz, 2H), 8.01 - 7.95 (m, 2H), 5.95 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 251 (R)-(1-methyl-4-(5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 550.0 1H NMR (400 MHz, methanol-d4) δ 9.47 (s, 2H), 8.95 (s, 1H), 8.25 (dd, J = 8.6, 2.6 Hz, 1H), 8.03 (s, 1H), 7.98 (dd, J = 8.7, 0.7 Hz, 1H), 7.87 (s, 1H), 5.95 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 252 (R)-(4-(5-(2-(difluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 532.0 1H NMR (400 MHz, methanol-d4) δ 9.42 (s, 2H), 9.01 - 8.87 (m, 1H), 8.25 (dd, J = 8.7, 2.6 Hz, 1H), 8.03 (s, 1H), 7.98 (dd, J = 8.7, 0.8 Hz, 1H), 7.83 (d, J = 45.1 Hz, 1H), 6.84 (t, J = 54.1 Hz, 1H), 5.95 (d, J = 6.8 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 253 (R)-(4-(5-(4-chloronicotinamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 515.0 1H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.78 (s, 1H), 8.62 (d, J = 5.5 Hz, 1H), 8.21 (dd, J = 8.7, 2.6 Hz, 1H), 8.02 (s, 1H), 8.00 - 7.94 (m, 2H), 7.66 (d, J = 5.5 Hz, 1H), 5.94 (d, J = 6.6 Hz, 1H), 3.99 (s, 3H), 1.60 (s, 3H). Compound 254 (R)-(4-(5-(2-fluoro-6-(trifluoromethyl)nicotinamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 566.9 1H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.54 (t, J = 8.1 Hz, 1H), 8.22 (dd, J = 8.7, 2.6 Hz, 1H), 8.03 (s, 1H), 7.98 (dd, J = 8.7, 0.8 Hz, 1H), 7.95 - 7.87 (m, 2H), 5.94 (d, J = 6.7 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 255 (R)-(4-(5-(4,6-difluoronicotinoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 517.0 1H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.65 (d, J = 9.7 Hz, 1H), 8.21 (dd, J = 8.7, 2.6 Hz, 1H), 8.02 (s, 1H), 8.00 - 7.73 (m, 2H), 7.16 (dd, J = 9.8, 1.7 Hz, 1H), 5.94 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 256 (R)-(1-methyl-4-(5-(2-methyloxazol-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 485.0 1H NMR (400 MHz, DMSO-d6) δ 10.59 (bs, 1H), 9.82 (bs, 1H), 8.85 (bs, 1H), 8.36-8.12 (m, 2H), 8.11 - 7.83 (m, 3H), 5.80 (bs, 1H), 3.89 (s, 3H), 2.56 (s, 3H), 1.57 (bs, 3H). Compound 257 (R)-(1-methyl-4-(5-(5-methyl-1,3,4-diazole-2-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 486.0 1H NMR (400 MHz, DMSO-d6) δ 11.47 (bs, 1H), 9.80 (bs, 1H), 8.91 (s, 1H), 8.39 - 8.11 (m, 2H), 8.11-7.64 (m, 2H), 5.80 (bs, 1H), 3.89 (s, 3H), 2.65 (s, 3H), 1.38 (d, J = 118.8 Hz, 3H). Compound 258 (R)-(4-(5-(3-cyanoisoxazole-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 495.9 1H NMR (400 MHz, DMSO-d6) δ 11.29 (bs, 1H), 9.83 (bs, 1H), 8.87 (s, 1H), 8.38 - 7.56 (m, 5H), 5.80 (bs, 1H), 3.90 (s, 3H), 1.56 (bs, 3H). Compound 259 (R)-(1-methyl-4-(5-(6-(trifluoromethyl)pyridin-4-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 550.0 1H NMR (400 MHz, methanol-d4) δ 9.91 (d, J = 2.0 Hz, 1H), 8.97 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.27 (dd, J = 8.7, 2.6 Hz, 1H), 8.03 (s, 1H), 8.01 - 7.64 (m, 2H), 5.95 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 260 (R)-(1-methyl-4-(5-(3-methylisoxazole-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 485.0 1H NMR (400 MHz, DMSO-d6) δ 10.99 (bs, 1H), 9.82 (bs, 1H), 8.89 (s, 1H), 8.38 - 7.69 (m, 4H), 7.16 (s, 1H), 5.78 (bs, 1H), 3.89 (s, 3H), 2.36 (s, 3H), 1.56 (bs, 3H). Compound 261 (R)-(4-(5-(3-fluoro-2-(trifluoromethyl)isoxanthamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 567.0 1H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.69 (d, J = 4.8 Hz, 1H), 8.21 (dd, J = 8.6, 2.6 Hz, 1H), 8.07 - 7.76 (m, 4H), 5.94 (d, J = 6.8 Hz, 1H), 3.99 (s, 3H), 1.60 (s, 3H). Compound 262 (R)-(4-(5-(6-chloro-2-fluoronicotinoylamino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 533.0 1H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.32 (dd, J = 9.1, 7.9 Hz, 1H), 8.20 (dd, J = 8.7, 2.6 Hz, 1H), 8.02 (s, 1H), 8.00 - 7.75 (m, 2H), 7.56 (dd, J = 7.9, 1.1 Hz, 1H), 5.94 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 1.60 (s, 3H). Compound 263 (R)-(4-(5-(4-chloro-5-fluoronicotinoylamino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 533.0 1H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.71 (d, J = 1.1 Hz, 1H), 8.65 (s, 1H), 8.21 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 (s, 1H), 8.00 - 7.76 (m, 2H), 5.94 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 264 (R)-(1-methyl-4-(5-(2,3,6-trifluoroisocyanamide)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 535.0 1H NMR (400 MHz, methanol-d4) δ 8.87 (s, 1H), 8.20 (dd, J = 8.6, 2.6 Hz, 1H), 8.07 - 7.71 (m, 3H), 7.36 (t, J = 2.9 Hz, 1H), 5.94 (d, J = 6.3 Hz, 1H), 3.99 (s, 3H), 1.60 (s, 3H). Compound 265 (R)-(1-methyl-4-(5-(1R,2R)-2-(pyridin-2-yl)cyclopropane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 521.0 1H NMR (400 MHz, methanol-d4) δ 8.80 (s, 1H), 8.58 - 8.32 (m, 1H), 8.27 - 7.60 (m, 5H), 7.40 (dd, J = 7.9, 1.0 Hz, 1H), 7.24 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 5.95 (s, 1H), 3.99 (s, 3H), 2.68 (ddd, J = 9.5, 6.2, 3.9 Hz, 1H), 2.51 - 2.28 (m, 1H), 1.85 - 1.51 (m, 5H). Compound 266 (R)-(1-methyl-4-(5-((1S,2S)-2-(pyridin-2-yl)cyclopropane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 521.0 1H NMR (400 MHz, methanol-d4) δ 8.80 (s, 1H), 8.52 - 8.38 (m, 1H), 8.22 - 7.60 (m, 5H), 7.48 - 7.32 (m, 1H), 7.24 (ddd, J = 7.6, 5.0, 1.2 Hz, 1H), 5.95 (s, 1H), 3.99 (s, 3H), 2.68 (ddd, J = 9.3, 6.1, 3.8 Hz, 1H), 2.39 (ddd, J = 9.1, 5.5, 3.9 Hz, 1H), 1.82 - 1.50 (m, 5H). Compound 267 (R)-(4-(5-((1S,2R)-[1,1'-bis(cyclopropane)]-2-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 484.0 1H NMR (400 MHz, methanol-d4) δ 8.77 (s, 1H), 8.39 - 7.53 (m, 4H), 5.94 (s, 1H), 3.99 (s, 3H), 1.56 (ddt, J = 72.3, 9.9, 4.5 Hz, 5H), 1.13 (dt, J = 9.0, 4.5 Hz, 1H), 0.94 (td, J = 8.2, 4.8 Hz, 1H), 0.84 - 0.71 (m, 1H), 0.57 - 0.36 (m, 2H), 0.22 (d, J = 4.9 Hz, 2H). Compound 268 (R)-(4-(5-((1R,2S)-[1,1'-bis(cyclopropane)]-2-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 484.0 1H NMR (400 MHz, methanol-d4) δ 8.78 (s, 1H), 8.26 - 7.62 (m, 4H), 5.94 (d, J = 6.1 Hz, 1H), 3.99 (s, 3H), 1.86 - 1.41 (m, 5H), 1.14 (dt, J = 9.0, 4.5 Hz, 1H), 0.94 (td, J = 8.2, 4.9 Hz, 1H), 0.85 - 0.72 (m, 1H), 0.63 - 0.37 (m, 2H), 0.21 (d, J = 5.0 Hz, 2H). Compound 269 (R)-(4-(5-((1R,2R)-1-cyano-2-fluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 487.0 1H NMR (400 MHz, methanol-d4) δ 8.68 (d, J = 89.1 Hz, 1H), 8.23 - 7.57 (m, 4H), 5.95 (d, J = 6.7 Hz, 1H), 5.26 (ddd, J = 62.8, 5.8, 4.4 Hz, 1H), 4.00 (d, J = 3.9 Hz, 3H), 2.32 - 2.12 (m, 2H), 1.62 (s, 4H). Compound 270 (R)-(4-(5-((1S,2S)-1-cyano-2-fluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 487.0 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 8.22 - 7.61 (m, 3H), 5.95 (s, 1H), 5.26 (ddd, J = 62.8, 5.9, 4.3 Hz, 1H), 4.00 (s, 3H), 2.32 - 2.07 (m, 2H), 1.62 (s, 3H). Compound 271 (R)-(4-(5-(6-(1-cyanocyclopropyl)nicotinamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 546.0 1H NMR (400 MHz, methanol-d4) δ 9.04 (dd, J = 2.4, 0.9 Hz, 1H), 8.94 (s, 1H), 8.35 (dd, J = 8.3, 2.3 Hz, 1H), 8.23 (dd, J = 8.7, 2.6 Hz, 1H), 8.02 (s, 1H), 7.98 - 7.90 (m, 1H), 7.92 - 7.75 (m, 2H), 5.94 (d, J = 6.9 Hz, 1H), 3.99 (s, 3H), 1.97 - 1.88 (m, 2H), 1.85 (p, J = 6.4, 5.9 Hz, 2H), 1.60 (s, 3H). Compound 272 (R)-(4-(5-(6-(1,1-difluoroethyl)nicotinoylamino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 545.0 1H NMR (400 MHz, methanol-d4) δ 9.18 (dd, J = 2.2, 0.9 Hz, 1H), 8.96 (s, 1H), 8.48 (dd, J = 8.2, 2.3 Hz, 1H), 8.25 (dd, J = 8.7, 2.6 Hz, 1H), 8.03 (s, 1H), 7.97 (dd, J = 8.6, 0.8 Hz, 1H), 7.93 - 7.69 (m, 2H), 5.94 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 2.04 (t, J = 18.7 Hz, 3H), 1.61 (s, 3H). Compound 273 (R)-(1-methyl-4-(5-(2-(methylsulfonyl)isonicotinoylamino)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 559.0 1H NMR (400 MHz, methanol-d4) δ 8.97 (dd, J = 5.0, 0.8 Hz, 1H), 8.60 (dd, J = 1.7, 0.8 Hz, 1H), 8.27 (dd, J = 8.7, 2.6 Hz, 1H), 8.20 (dd, J = 5.0, 1.7 Hz, 1H), 8.03 (s, 1H), 8.00 - 7.75 (m, 2H), 5.94 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 3.30 (s, 3H), 1.61 (s, 3H). Compound 274 (R)-(1-methyl-4-(5-(1-methyl-1H-benzo[d]imidazol-6-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 534.0 1H NMR (400 MHz, methanol-d4) δ 8.99 (s, 1H), 8.32 (s, 1H), 8.27 (dd, J = 8.8, 2.3 Hz, 2H), 8.02 (s, 1H), 7.99 - 7.83 (m, 3H), 7.80 (d, J = 8.5 Hz, 1H), 5.95 (d, J = 7.1 Hz, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 275 (R)-(4-(5-(2-fluoro-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 567.0 1H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.78 (d, J = 2.3 Hz, 1H), 8.66 (dd, J = 8.1, 2.5 Hz, 1H), 8.23 (dd, J = 8.6, 2.6 Hz, 1H), 8.03 (s, 1H), 8.00 - 7.68 (m, 2H), 5.94 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H). Compound 276 (R)-(4-(5-(3,4-dimethylisoxazole-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 499.0 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.82 (bs, 1H), 8.90 (s, 1H), 8.33 - 7.80 (m, 4H), 5.80 (bs, 1H), 3.89 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H), 1.58 (bs, 3H). Compound 277 (R)-(1-methyl-4-(5-(2-methyl-3H-imidazo[4,5-b]pyridine-6-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 535.0 1H NMR (400 MHz, methanol-d4) δ 8.97 (s, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.26 (dd, J = 8.6, 2.6 Hz, 1H), 8.03 (s, 1H), 8.00 - 7.77 (m, 2H), 5.95 (s, 1H), 3.99 (s, 3H), 2.68 (s, 3H), 1.61 (s, 3H). Compound 278 (R)-(1-methyl-4-(5-(1-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 535.0 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.81 (s, 1H), 9.08 (d, J = 1.9 Hz, 1H), 8.93 (s, 1H), 8.77 (t, J = 1.4 Hz, 1H), 8.42 (d, J = 1.0 Hz, 1H), 8.33 - 8.12 (m, 2H), 8.08 - 7.87 (m, 2H), 5.81 (s, 1H), 4.20 (s, 3H), 3.88 (s, 3H), 1.54 (s, 3H). Compound 279 (R)-(1-methyl-4-(5-(3-methylbenzo[d]isoxazole-6-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 535.0 1H NMR (400 MHz, methanol-d4) δ 8.98 (s, 1H), 8.26 (dd, J = 8.6, 2.6 Hz, 1H), 8.21 (t, J = 1.0 Hz, 1H), 8.02 (s, 1H), 8.00 - 7.80 (m, 4H), 5.95 (d, J = 6.9 Hz, 1H), 3.99 (s, 3H), 2.64 (s, 3H), 1.61 (s, 3H). Compound 280 (R)-(4-(5-(2-cyclopropyloxazol-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 511.0 1H NMR (400 MHz, DMSO-d6) δ 10.47 (bs, 1H), 9.80 (bs, 1H), 8.84 (s, 1H), 8.34 - 8.09 (m, 2H), 8.09 - 7.65 (m, 3H), 5.79 (bs, 1H), 3.88 (s, 3H), 2.30-2.18 (m, 1H), 1.53 (bs, 3H), 1.21 - 1.00 (m, 4H). Compound 281 (R)-(4-(5-(3-methoxyisoxazole-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 501.0 1H NMR (400 MHz, DMSO-d6) δ 10.97 (bs, 1H), 9.82 (bs, 1H), 8.87 (s, 1H), 8.36 - 7.65 (m, 4H), 7.06 (s, 1H), 5.80 (bs, 1H), 3.99 (s, 3H), 3.89 (s, 3H), 1.54 (bs, 3H). Compound 282 (R)-(4-(5-(2-(dimethylamino)pyrimidine-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 524.9 1H NMR (400 MHz, methanol-d4) δ 8.90 (s, 2H), 8.19 (dd, J = 8.6, 2.6 Hz, 1H), 8.10 - 7.99 (m, 2H), 7.97 - 7.69 (m, 2H), 5.94 (d, J = 7.1 Hz, 1H), 3.98 (s, 3H), 3.28 (s, 6H), 1.60 (s, 3H). Compound 283 (R)-(4-(5-(2-cyclopropylpyrimidine-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 522.0 1H NMR (400 MHz, methanol-d4) δ 9.12 (s, 2H), 8.93 (s, 1H), 8.23 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 (s, 1H), 7.99 - 7.76 (m, 2H), 5.94 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 2.42 - 2.26 (m, 1H), 1.61 (s, 3H), 1.22 (tt, J = 8.1, 2.9 Hz, 4H). Compound 284 (R)-(1-methyl-4-(5-(2-oxopyrimidine-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 567.0 1H NMR (400 MHz, methanol-d4) δ 8.92 (s, 2H), 8.19 (dd, J = 8.7, 2.6 Hz, 1H), 8.09 - 7.99 (m, 2H), 7.98 - 7.76 (m, 2H), 5.94 (d, J = 6.8 Hz, 1H), 3.99 (s, 3H), 3.94 (dd, J = 5.6, 4.2 Hz, 4H), 3.80 - 3.71 (m, 4H), 1.61 (s, 3H). Compound 285 (R)-(4-(5-((1RS,2RS)-2-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester 485.1 1H NMR (400 MHz, methanol-d4) δ 9.13 - 8.76 (m, 1H), 8.43 - 8.07 (m, 2H), 7.93 (m, 2H), 6.03 (m 1H), 4.01 (s, 3H), 2.48 (m, 1H), 2.12 (m, 1H), 1.84 - 1.32 (m, 5H). Compound 288 (R)-(1-methyl-4-(5-(6-(trifluoromethyl)nicotinamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester 565.0 1H NMR (400 MHz, methanol-d4) δ 9.26 (d, J = 2.1 Hz, 1H), 8.97 (s, 1H), 8.64 - 8.52 (m, 1H), 8.34 - 8.15 (m, 2H), 8.11 - 7.68 (m, 3H), 6.03 (d, J = 7.2 Hz, 1H), 4.00 (s, 3H), 1.60 (s, 3H). Compound 289 (R)-(4-(5-(2-(difluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester 548.0 1H NMR (400 MHz, methanol-d4) δ 9.42 (s, 2H), 8.97 (s, 1H), 8.24 (dd, J = 8.7, 2.6 Hz, 2H), 8.03 - 7.71 (m, 2H), 6.84 (t, J = 54.2 Hz, 1H), 6.03 (s, 1H), 3.99 (s, 3H), 1.60 (s, 3H). Compound 290 (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate 566.0 1H NMR (400 MHz, methanol-d4) δ 9.47 (s, 2H), 8.97 (s, 1H), 8.37 - 8.14 (m, 2H), 8.05 - 7.66 (m, 2H), 6.03 (d, J = 7.0 Hz, 1H), 4.00 (s, 3H), 1.60 (s, 3H). Compound 291 (R)-(4-(5-(3,3-difluoro-1-methylcyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester 490.1 1H NMR (400 MHz, methanol-d4) δ 8.96 (m, 1H), 8.34 - 7.99 (m, 3H), 7.93 (m, 1H), 7.39 (s, 1H), 6.00 (m, 1H), 4.00 (s, 3H), 3.25 - 3.05 (m, 2H), 2.68 - 2.45 (m, 2H), 1.65 (s, 6H). Compound 292 (R)-(4-(5-(6-chloronicotinamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester 496.9 1H NMR (400 MHz, methanol-d4) δ 8.96 (dd, J = 2.6, 0.7 Hz, 2H), 8.36 (dd, J = 8.4, 2.6 Hz, 1H), 8.21 (dd, J = 8.6, 2.6 Hz, 1H), 8.16 - 8.06 (m, 2H), 7.99 - 7.90 (m, 1H), 7.64 (dd, J = 8.3, 0.7 Hz, 1H), 7.36 (s, 1H), 5.99 (d, J = 6.8 Hz, 1H), 3.98 (s, 3H), 1.61 (s, 3H). Compound 293 (R)-(4-(5-(2-chloroisocyanamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester 497.0 1H NMR (400 MHz, methanol-d4) δ 8.99 (s, 1H), 8.61 (dd, J = 5.1, 0.8 Hz, 1H), 8.24 (dd, J = 8.6, 2.6 Hz, 1H), 8.18 - 8.11 (m, 2H), 8.05 - 7.95 (m, 2H), 7.89 (dd, J = 5.1, 1.5 Hz, 1H), 7.38 (s, 1H), 6.01 (d, J = 7.1 Hz, 1H), 4.00 (s, 3H), 1.63 (s, 3H). Compound 294 (R)-(4-(5-(2,3-difluoroisocyanamide)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester 499.0 1H NMR (400 MHz, methanol-d4) δ 8.91 (s, 1H), 8.27 - 8.10 (m, 4H), 7.97 (dd, J = 8.7, 0.7 Hz, 1H), 7.62 (dd, J = 5.0, 4.1 Hz, 1H), 7.36 (s, 1H), 5.99 (d, J = 6.7 Hz, 1H), 3.98 (s, 3H), 1.61 (s, 3H). Compound 295 (R)-(4-(5-(6-(difluoromethyl)nicotinamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester 513.0 1H NMR (400 MHz, methanol-d4) δ 9.21 (d, J = 2.0 Hz, 1H), 8.98 (s, 1H), 8.53 (dd, J = 8.1, 2.2 Hz, 1H), 8.23 (dd, J = 8.7, 2.6 Hz, 1H), 8.16 - 8.08 (m, 2H), 7.96 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H), 6.83 (t, J = 55.0 Hz, 1H), 5.99 (d, J = 6.9 Hz, 1H), 3.98 (s, 3H), 1.61 (s, 3H). Compound 296 (R)-(1-methyl-4-(5-(6-(trifluoromethyl)nicotinamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-fluoropyridin-3-yl)ethyl ester 531.0 1H NMR (400 MHz, methanol-d4) δ 9.27 (d, J = 2.1 Hz, 1H), 8.98 (s, 1H), 8.58 (dd, J = 8.2, 2.2 Hz, 1H), 8.27 - 8.19 (m, 1H), 8.17 - 8.07 (m, 2H), 7.99 (dd, J = 16.5, 8.4 Hz, 2H), 7.36 (s, 1H), 5.99 (d, J = 6.6 Hz, 1H), 3.98 (s, 3H), 1.61 (s, 3H). Examples 55 : Preparation (R)-(4-(5-((1r,3R)-3- Cyano -3- Fluorocyclobutane -1- Formamide ) Pyridine -2- base )-1- methyl -1H-1,2,3- Triazole -5- base ) Carbamic acid 1-(2- Chloropyridine -3- base ) Ethyl ester ( Compound 185)

To a solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((1s,3S)-3-cyano-3-hydroxycyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 139) (0.04 mmol) in stirred dichloromethane (1 mL) was added sulfur trifluoride (diethylamino) (0.04 mmol) at 0°C. It was slowly warmed to room temperature and stirred for 12 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate solution and brine. The aqueous layer was extracted with dichloromethane, and the combined organic extracts were dried over (sodium sulfate), filtered and concentrated in vacuo to give the title compound as a slightly yellow oil. The residue was purified by reverse phase HPLC to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-((1r,3R)-3-cyano-3-fluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 185). (MS ( m/z ) 499.1 [M+H] ⁺ ). 1H NMR (400 MHz, methanol-d4) δ 8.92 (s, 1H), 8.32 (s, 1H), 8.21 - 7.78 (m, 3H), 7.39 (d, 1H), 6.21 - 5.92 (m, 1H), 5.01 - 4.65 (m, 2H), 4.00 (s, 3H), 2.76 (m, 1H), 1.94 - 1.79 (m, 2H), 1.55 (d, 3H). Example 56 : Preparation of (R)-(4-(5-(1- cyano -3,3 -difluorocyclobutane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 186)

To a solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(1-cyano-3-oxocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (20 mg, 0.04 mmol) in stirred dichloromethane (1 mL) was added (diethylamino)sulfur trifluoride (30 mg, 0.19 mmol) at 0°C. It was slowly warmed to room temperature and stirred for 12 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate solution. The mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC to give (R)-(4-(5-(1-cyano-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester (Compound 186). (MS ( m/z ) 517.0 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.10 - 8.82 (m, 1H), 8.33 (s, 1H), 8.29 - 8.02 (m, 2H), 7.97 (d, 1H), 7.51 (s, 1H), 6.09 (d, 1H), 4.02 (d, 3H), 3.57 (m, 2H), 3.33 (m, 2H), 1.65 (s, 3H). Example 57 : Preparation of 2 - fluoro -1-(3-fluorophenyl ) ethyl (1- methyl -4-(5-(3- methylureido ) pyridin -2- yl )-1H-1,2,3 - triazole - 5- ) carbamate ( Compound 187)

(S)-2-Fluoro-1-(3-fluorophenyl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 6B) (0.05 mmol) was dissolved in dichloromethane (1 mL), pyridine (0.2 mL). Triphosgene (0.1 mmol) was added and after 10 minutes a solution of 2 M methylamine (0.5 mmol) in THF was added. After 30 min, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 1 M aqueous sodium hydroxide solution (2 mL) and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by reverse phase HPLC to give (S)-2-fluoro-1-(3-fluorophenyl)ethyl (1-methyl-4-(5-(3-methylureido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 187). (MS ( m/z ) 432.2 [M+H] ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.81 (s, 1H), 8.02 (dd, J = 8.7, 2.4 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.61 - 6.59 (m, 4H), 6.14 - 5.62 (m, 1H), 4.78 - 4.39 (m, 2H), 3.98 (s, 3H), 2.80 (s, 3H). Example 58 : Preparation of Compounds 188 to 194

Compounds 188 to 194 were generally synthesized according to Scheme C, step 4. For example, (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(aza-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 188) was prepared as follows.

(R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 5A) (Example 21) (0.07 mmol) was dissolved in 0.2 mL DCM and 0.1 mL DMF and treated with triethyl-amine (0.183 mmol) and phenyl chloroformate (0.08 mmol). The reaction was stirred for 15 min and acrylamide (0.112 mmol) was added as a solution in THF. After 15 min, the reaction was concentrated, then dissolved in aqueous MeCN and acidified with TFA. Purification by RP-HPLC gave (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(aza-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 188) as a TFA salt (MS (m/z) 457.1 [M+H]+). 1H NMR (400 MHz, acetonitrile-d3) δ 8.93 (s, 1H), 8.59 (bs, 1H), 8.34 (dd, J = 4.8, 1.9 Hz, 1H), 8.14 (ddd, J = 8.8, 2.6, 1.2 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 15.7 Hz, 2H), 6.04 (q, J = 6.6 Hz, 1H), 4.14 - 4.05 (m, 4H), 3.96 (s, 3H), 2.31 (dq, J = 8.2, 7.4 Hz, 2H), 1.59 (d, J = 6.6 Hz, 3H).

Compounds 188-194 (Table 3) were prepared similarly according to Scheme C, Step 4, following the general procedure described for compound 188 by reacting (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester, Intermediate 5A (Example 21) with the reagents listed in Table 3 instead of acridine. Table 3 : Compounds prepared according to Scheme C , Step 4 . Compound No. Structure Reagent LCMS m/z 1H NMR Compound 188 (R)-(4-(5-(aza-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 457.1 1H NMR (400 MHz, acetonitrile-d3) δ 8.93 (s, 1H), 8.59 (bs, 1H), 8.34 (dd, J = 4.8, 1.9 Hz, 1H), 8.14 (ddd, J = 8.8, 2.6, 1.2 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 15.7 Hz, 2H), 6.04 (q, J = 6.6 Hz, 1H), 4.14 - 4.05 (m, 4H), 3.96 (s, 3H), 2.31 (dq, J = 8.2, 7.4 Hz, 2H), 1.59 (d, J = 6.6 Hz, 3H). Compound 189 (R)-(4-(5-(3-cyanobicyclo[1.1.1]pentane-1-carboxamido)-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 487.1 1H NMR (400 MHz, acetonitrile-d3) δ 8.90 (d, J = 22.7 Hz, 1H), 8.62 (s, 1H), 8.35 (dd, J = 4.8, 1.9 Hz, 1H), 8.19 - 8.07 (m, 1H), 7.99 (dd, J = 8.8, 2.2 Hz, 1H), 7.92 (s, 1H), 7.68 (d, J = 34.5 Hz, 1H), 7.41 (s, 1H), 6.04 (q, J = 6.6 Hz, 1H), 3.96 (s, 3H), 3.71 (dd, J = 5.6, 4.1 Hz, 3H), 3.51 (t, J = 4.9 Hz, 4H), 1.95 (s, 0H), 1.59 (d, J = 6.6 Hz, 3H). Compound 190 (R)-(1-methyl-4-(5-((R)-3-methylpyrrolidine-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 485.1 1H NMR (400 MHz, acetonitrile-d3) d 9.08 (s, 1H), 8.34 (dd, J = 4.8, 1.9 Hz, 1H), 8.24 (dd, J = 8.9, 2.4 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.54 (s, 1H), 7.42 (s, 2H), 6.03 (q, J = 6.6 Hz, 1H), 3.96 (s, 3H), 3.70 - 3.54 (m, 2H), 2.99 (dd, J = 9.9, 8.1 Hz, 1H), 2.35 (t, J = 7.4 Hz, 1H), 2.14 - 2.05 (m, 1H), 2. (s, 1H), 1.68 - 1.55 (m, 4H), 1.11 (d, J = 6.6 Hz, 3H). Compound 191 (R)-(4-(5-(3-cyanoacrylamide-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 482.1 1H NMR (400 MHz, acetonitrile-d3) δ 8.79 (m, 2H), 8.47 (s, 1H), 8.15 (d, J = 20.4 Hz, 1H), 8.05 (dd, J = 8.7, 2.4 Hz, 1H), 8.00 (s, 1H), 7.06 (s, 1H), 5.90 (q, J = 6.6 Hz, 1H), 3.96 (t, J = 1.0 Hz, 3H), 2.31 (s, 3H), 1.78 - 1.68 (m, 5H), 1.54 (d, J = 6.1 Hz, 3H). Compound 192 (R)-(1-methyl-4-(5-((R)-2-methylpyrrolidine-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 485.1 1H NMR (400 MHz, acetonitrile-d3) δ 9.01 (d, J = 2.4 Hz, 1H), 8.78 (s, 1H), 8.34 (dd, J = 4.8, 1.9 Hz, 1H), 8.21 (dd, J = 8.8, 2.5 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.40 (s, 1H), 6.04 (q, J = 6.6 Hz, 1H), 4.13 (pd, J = 6.4, 2.8 Hz, 1H), 3.96 (s, 3H), 3.55 (ddd, J = 9.9, 7.5, 3.6 Hz, 1H), 3.50 - 3.39 (m, 1H), : 2.07 (dddd, J = 13.6, 10.9, 5.7, 4.0 Hz, 2H), 1.95 (d, J = 1.7 Hz, 0H), 1.73 - 1.61 (m, 1H), 1.59 (d, J = 5.9 Hz, 3H), 1.24 (d, J = 6.3 Hz, 3H). Compound 193 (R)-(4-(5-(3,3-difluoropyrrolidine-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 507.1 1H NMR (400 MHz, acetonitrile-d3) d 8.91 (s, 1H), 8.58 (s, 0H), 8.35 (dd, J = 4.7, 1.8 Hz, 1H), 8.15 (dd, J = 8.8, 2.4 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 7.42 (s, 1H), 6.04 (q, J = 6.6 Hz, 1H), , 3.96 (s, 3H), 3.86 (t, J = 13.1 Hz, 2H), 3.73 (t, J = 7.4 Hz, 2H), 2.51 (tt, J = 14.3, 7.4 Hz, 2H), 1.58 (s, 3H). Compound 194 (R)-(1-methyl-4-(5-(pyrrolidine-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester 471.1 1H NMR (400 MHz, acetonitrile-d3) d 9.08 (s, 1H), 8.34 (dd, J = 4.8, 1.9 Hz, 1H), 8.24 (dd, J = 8.9, 2.4 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.54 (s, 1H), 7.42 (s, 2H), 6.03 (q, J = 6.6 Hz, 1H), 3.96 (s, 3H), 3.70 - 3.54 (m, 2H), 2.99 (dd, J = 9.9, 8.1 Hz, 1H), 2.35 (t, J = 7.4 Hz, 1H), 2.14 - 2.05 (m, 1H), 2. (s, 1H), 1.68 - 1.55 (m, 4H), 1.11 (d, J = 6.6 Hz, 3H). Example 59 : Preparation of compounds 297 to 303

Compounds 297 to 304 were generally synthesized according to Scheme C, step 4, followed by removal of the protecting group. For example, (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3-cyanoazide-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 297) was prepared as follows. Step 1 : (R)-3- cyano -3-((6-(5-(((1-(2,5 -difluoropyridin -3 -yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyridin -3- yl ) aminocarbonyl ) acryl -1- carboxylic acid tributyl ester

A vial was charged with (R)-ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate 1-(2,5-difluoropyridin-3-yl) ester hydrochloride (Intermediate 5B) (0.12 mmol), 1-(tert-butyloxycarbonyl)-3-cyanoacridine-3-carboxylic acid (0.15 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.24 mmol) and pyridine (2 mL). The reaction mixture was stirred at room temperature for 2 h, concentrated, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated to give (R)-3-cyano-3-((6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)aminocarbonyl)acryl-1-carboxylic acid tributyl ester which was used without further purification. (MS ( m/z ) 584.3 [M+H] ⁺ ). Step 2 : (R)-(4-(5-(3- cyanoacrylamide -3- carboxamido ) pyridin - 2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3 - yl ) ethyl ester

A solution of (R)-tributyl 3-cyano-3-((6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamyl)azetidine-1-carboxylate (0.12 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at room temperature for 1 hour. The reaction was concentrated and purified by reverse phase HPLC to give 1-(2,5-difluoropyridin-3-yl)ethyl 3-cyano-3-((6-(5-((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamyl)azetidine-1-carboxylate as the trifluoroacetate salt. (MS ( m/z ) 484.0 [M+H] ⁺ ). 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.85 (bs, 1H), 9.31 (bs, 2H), 8.69 (bs, 1H), 8.20 (bs, 1H), 8.11 - 7.83 (m, 3H), 5.80 (bs, 1H), 4.53 (q, J = 11.4 Hz, 4H), 3.90 (s, 3H), 1.41 (bs, 3H).

Compounds 298-303 (Table 4) were prepared similarly according to Scheme C, Step 4 by reacting (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 5B) (Example 22) with the reagents listed in Table 4 instead of 1-(tert-butyloxycarbonyl)-3-cyanoacridine-3-carboxylic acid. Table 4 : Compounds prepared according to Scheme C , Step 4 . Compound No. Structure Reagent LCMS m/z 1H NMR Compound 297 (R)-(4-(5-(3-cyanoacrylamide-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 484.0 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.85 (bs, 1H), 9.31 (bs, 2H), 8.69 (bs, 1H), 8.20 (bs, 1H), 8.11 - 7.83 (m, 3H), 5.80 (bs, 1H), 4.53 (q, J = 11.4 Hz, 4H), 3.90 (s, 3H), 1.41 (bs, 3H). Compound 298 (R)-(4-(5-(3-(difluoromethyl)azepine-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 509.2 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.84 (bs, 1H), 9.20 (bs, 1H), 8.87 (bs, 1H), 8.71 (bs, 1H), 8.35-7.75 (m, 4H), 6.63 (t, J = 55.1 Hz, 1H), 5.79 (bs, 1H), 4.51 - 4.30 (m, 2H), 4.29-4.10 (m, 2H), 3.89 (s, 3H), 1.81 - 1.07 (bs, 3H). Compound 299 (R)-(4-(5-(4-cyanopiperidine-4-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 512.1 1H NMR (400 MHz, DMSO-d6) δ 11.95 (bs, 1H), 10.66 (s, 1H), 9.84 (bs, 1H), 8.97 - 8.40 (m, 3H), 8.34 - 7.89 (m, 3H), 5.79 (bs, 1H), 3.90 (s, 3H), 3.56-3.37 (m, 2H), 3.22-3.01 (m, 2H), 2.49 - 2.39 (m, 2H), 2.37 - 2.19 (m, 2H), 1.58 (bs, 3H). Compound 300 (R)-(4-(5-(1-(aminomethyl)-2,2-difluorocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 509.0 1H NMR (400 MHz, DMSO-d6) δ 10.43 (d, J = 4.4 Hz, 1H), 9.83 (bs, 1H), 8.77-8.65 (m, 1H), 8.42-7.80 (m, 5H), 5.80 (bs, 1H), 3.89 (s, 3H), 3.79 (dd, J = 14.1, 5.3 Hz, 1H), 3.08 (dd, J = 13.7, 6.1 Hz, 1H), 2.47 (m, 1H), 2.24 - 2.06 (m, 1H), 1.57 (bs, 3H). Compound 301 (R)-(4-(5-(1-(aminomethyl)-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 523.0 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.82 (bs, 1H), 8.74 (s, 1H), 8.32 - 7.74 (m, 7H), 5.80 (bs, 1H), 3.89 (s, 3H), 3.53-3.34 (m, 2H), 3.20 (q, J = 13.3 Hz, 2H), 2.90 (q, J = 12.6 Hz, 2H), 1.56 (bs, 3H). Compound 302 (R)-(4-(5-(3-cyanopyrrolidine-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 498.0 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.84 (bs, 1H), 9.37 (bs, 2H), 8.71 (s, 1H), 8.37-7.79 (m, 4H), 5.79 (bs, 1H), 4.00 (d, J = 12.6 Hz, 1H), 3.92 - 3.82 (m, 4H), 3.52-3.41 (m, 1H), 3.42 - 3.30 (m, 1H), 2.75 (t, J = 7.2 Hz, 2H), 1.58 (bs, 3H). Compound 303 (R)-(4-(5-(1-(aminomethyl)cyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester 487.1 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.82 (bs, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.21 (bs, 1H), 8.13 (dd, J = 8.7, 2.5 Hz, 1H), 8.03 (bs, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.85 (bs, 3H), 5.80 (bs, 1H), 3.89 (s, 3H), 3.40-3.28 (m, 2H), 2.59 - 2.52 (m, 2H), 2.18 - 1.93 (m, 3H), 1.93-1.78 (m, 1H), 1.55 (bs, 3H). Example 60 : Preparation of (R)-(4-(5-(1-( aminomethyl )-3,3 -difluorocyclobutane -1 -carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin -3- yl ) ethyl ester ( Compound 304) Step 1 : (R)-(4-(5-(1-((( tributyloxycarbonyl ) amino ) methyl )-3,3 -difluorocyclobutane -1 - carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin -3- yl ) ethyl ester

A vial was charged with (R)-ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate 1-(2-chloro-5-fluoropyridin-3-yl) hydrochloride (Intermediate 5C) (0.19 mmol), 1-(((tert-butyloxycarbonyl)amino)methyl)-3,3-difluorocyclobutane-1-carboxylic acid (0.25 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 mmol) and pyridine (2 mL). The reaction mixture was stirred at room temperature for 2 h, concentrated, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated to give 1-(2-chloro-5-fluoropyridin-3-yl)ethyl (R)-(4-(5-(1-(((tributyloxycarbonyl)amino)methyl)-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate which was used without further purification. (MS ( m/z ) 639.1. [M+H] ⁺ ). Step 2 : (R)-(4-(5-(1-( aminomethyl )-3,3 -difluorocyclobutane -1 -carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin -3- yl ) ethyl ester

A solution of (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(1-(((tributyloxycarbonyl)amino)methyl)-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.12 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at room temperature for 18 h. The reaction was concentrated and purified by reverse phase HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(1-(aminomethyl)-3,3-difluorocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a trifluoroacetate salt (MS ( m/z ) 539.0 [M+H] ⁺ ). 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.87 (bs, 1H), 8.76 (s, 1H), 8.44 (bs, 1H), 8.15 - 7.68 (m, 5H), 5.84 (bs, 1H), 3.90 (s, 3H), 3.51-3.22 (m, 2H), 3.21 (q, J = 13.3 Hz, 2H), 2.90 (q, J = 13.0 Hz, 2H), 1.57 (bs, 3H). Example 61 : Preparation of (R)-1- (2,5-difluoropyridin-3-yl)ethyl (4-(5-(3-cyano-1- ( 2,2,2-trifluoroethyl) azetidine - 3 - carboxamido ) pyridin - 2 - yl )-1 - methyl -1H-1,2,3 - triazol - 5 - yl ) carbamate ( Compound 305 )

A vial was charged with (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3-cyanoazide-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as trifluoroacetate (0.03 mmol), triethylamine (0.15 mmol), and ACN (2 mL). 2,2,2-Trifluoroethyl triflate (0.09 mmol) was added and the solution was heated at 60 °C for 2 h. The reaction was concentrated and purified by reverse phase HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3-cyano-1-(2,2,2-trifluoroethyl)azetidine-3-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS ( m/z ) 565.9 [M+H] ⁺ ). 1H NMR (400 MHz, DMSO-d6) δ 10.77 (bs, 1H), 9.84 (bs, 1H), 8.70 (bs, 1H), 8.19 (bs, 1H), 8.13-7.91 (m, 3H), 5.80 (bs, 1H), 3.96 (d, J = 7.6 Hz, 2H), 3.93-3.86 (m, 5H), 3.37 (q, J = 10.1 Hz, 2H), 1.58 (bs, 3H). Example 62 : Preparation of (R)-(1- methyl -4-(5-((1r,3R)-3-((2,2,2- trifluoroethyl ) amino ) cyclobutane -1- carboxamido ) pyridin -2- yl )-1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 306) Step 1 : (R)-1-( 2-chloropyridin- 3-yl )ethyl(4-(5-((1r,3R)-3-(( tert -butyloxycarbonyl ) amino ) cyclobutane -1 - carboxamido ) pyridin -2 - yl ) -1 - methyl - 1H - 1,2,3 - triazol - 5 - yl ) carbamate .

(R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (0.146 mmol) suspended in dimethylformamide (2 mL) was treated with (1r,3r)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (0.186 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.438 mmol) and pyridine (0.869 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give the crude product. Step 2 : (R)-(4-(5-(1r,3R)-3- aminocyclobutane -1 -carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester

(R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((1r,3R)-3-((tributyloxycarbonyl)amino)cyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.105 mmol) dissolved in dichloromethane (2 mL) was treated with trifluoroacetic acid (10.5 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was redissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The layers were separated. The organic layer was concentrated to give the crude product. Step 3 : (R)-1-(2-chloropyridin-3-yl)ethyl(1- methyl - 4-(5-((1r,3R)-3-((2,2,2-trifluoroethyl)amino)cyclobutane - 1 - carboxamido ) pyridin - 2 - yl ) -1H - 1,2,3 - triazol - 5 - yl ) carbamate

(R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((1r,3R)-3-aminocyclobutane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.0425 mmol) dissolved in acetonitrile (4 mL) was treated with triethylamine (0.215 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.144 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was purified by HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-((1r,3R)-3-((2,2,2-trifluoroethyl)amino)cyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 553.1 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.86 (s, 1H), 8.39 - 8.24 (m, 2H), 8.09 (dd, J = 8.5, 2.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 7.7, 4.8 Hz, 1H), 6.07 (s, 1H), 4.16 (p, J = 8.0 Hz, 1H), 3.99 (s, 3H), 3.94 (t, J = 9.1 Hz, 1H), 2.74 (td, J = 8.6, 8.1, 4.1 Hz, 2H), 2.57 (dt, J = 13.6, 9.3 Hz, 2H), 1.55 (d, J = 46.0 Hz, 3H). Example 63 : Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl(1- methyl - 4- ( 5-((1s,3S)-3-((2,2,2- trifluoroethyl ) amino ) cyclobutane -1 - carboxamido ) pyridin -2- yl )-1H-1,2,3- triazol -5 - yl ) carbamate ( Compound 307 )

The title compound was prepared in analogy to Example 62 using ((1s,3s)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid (0.186 mmol) instead of (1r,3r)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid. (MS (m/z) 553 [M+H]+). 1H NMR (400 MHz, Methanol-d4) δ 8.84 (s, 1H), 8.31 (s, 1H), 8.09 (dd, J = 8.7, 2.6 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.46 (s, 2H), 6.07 (s, 1H), 3.99 (s, 3H), 3.82 - 3.69 (m, 3H), 3.11 (d, J = 8.5 Hz, 2H), 2.74 - 2.60 (m, 2H), 2.43 (d, J = 10.6 Hz, 2H), 1.61 (s, 3H). Example 64 : Preparation of (R)-(1- methyl -4-(5-((1R,5R,6r)-3-(2,2,2- trifluoroethyl )-3- azabicyclo [3.1.0] hexane -6- carboxamido ) pyridin -2- yl )-1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 308)

The title compound was prepared similarly to Example 62 using exo-3-((tert-butyloxy)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (0.186 mmol) instead of (1r,3r)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid. (MS (m/z) 565.1 [M+H]+). 1H NMR (400 MHz, Methanol-d4) δ 8.95 (s, 1H), 8.33 (s, 1H), 8.13 (d, J = 7.8 Hz, 2H), 7.90 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 6.09 (d, J = 6.9 Hz, 1H), 4.00 (s, 2H), 3.24 (dt, J = 19.5, 9.5 Hz, 4H), 2.87 - 2.76 (m, 2H), 2.21 (t, J = 2.9 Hz, 1H), 2.10 (t, J = 2.7 Hz, 2H), 1.63 (s, 3H). Example 65 : Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (1- methyl - 4-(5-(1-(2,2,2- trifluoroethyl ) azabi -3 - carboxamido ) pyridin -2- yl ) -1H - 1,2,3 - triazol - 5 - yl ) carbamate ( Compound 309 )

The title compound was prepared analogously to Example 62 using 1-(tert-butyloxycarbonyl)azetidine-3-carboxylic acid (0.186 mmol) instead of (1r,3r)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid. (MS (m/z) 539.1 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 8.33 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 4.43 (d, J = 7.8 Hz, 2H), 4.13 (d, J = 9.1 Hz, 2H), 4.00 (s, 2H), 3.86 (q, J = 8.0 Hz, 1H), 1.62 (s, 3H). Example 66 : Preparation of (R)-(4-(5-(1- amino -3,3 -difluorocyclobutane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 310) Step 1 : (R)-(4-(5-(1-(( tributyloxycarbonyl ) amino )-3,3 -difluorocyclobutane -1 - carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester

A mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (25 mg, 0.061 mmol), 1-((tert-butyloxycarbonyl)amino)-3,3-difluorocyclobutane-1-carboxylic acid (31 mg, 0.122 mmol), EDCI (20 mg, 0.1 mmol) in pyridine (1 ml) was stirred at room temperature for 1 h. The residue was purified by preparative HPLC using Gilson preparative HPLC (Gemini column, 30%-85% CH ₃ CN in H ₂ O and 0.1% TFA) to give an intermediate. MS: 607.15 (M+1). Step 2 : (R) -1-(2- chloropyridin - 3- yl ) ethyl(4-(5-(1- amino -3,3 -difluorocyclobutane -1 - carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3 - triazole -5-) carbamate.

The above intermediate (20 mg) was treated with 2 mL of 4 N HCl in dioxane and the mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was purified by preparative HPLC using Gilson preparative HPLC (Gemini column, 30%-85% CH ₃ CN in H ₂ O and 0.1% TFA) to give the product. (MS (m/z) 507 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.32 (s, 1H), 8.15 (m, 1H), 7.95 (m, 1H), 7.68 - 7.25 (m, 2H), 6.08 (s, 1H), 4.00 (s, 3H), 3.72 (m, 2H), 3.19 (m, 2H), 1.86 - 1.40 (m, 3H). Example 67 : Synthesis of (R)-(4-(5-(3-( cyclopropylamino ) cyclobutane -1 - carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 311) Step 1. (R) -1-(2- chloropyridin -3- yl ) ethyl (1- methyl -4-(5-(3 -oxocyclobutane -1 -carboxamido ) pyridin - 2 -yl )-1H-1,2,3- triazol -5- yl ) carbamate

(R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloropyridin-3-yl)ethyl ester hydrochloride (0.0975 mmol) suspended in dimethylformamide (2 mL) was treated with 3-oxocyclobutane-1-carboxylic acid (0.131 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.292 mmol) and pyridine (0.621 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and washed with water. The layers were separated. The organic layer was concentrated to give crude (R)-1-(2-chloropyridin-3-yl)ethyl (1-methyl-4-(5-(3-oxocyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5- yl ) carbamate. Step 2. (R)-1-(2-chloropyridin-3-yl)ethyl (1 - methyl - 4-(5-(3 - oxocyclobutane -1 - carboxamido ) pyridin -2- yl )-1H-1,2,3- triazol -5 - yl ) carbamate

(R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(3-oxocyclobutane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (0.0638 mmol) suspended in dichloromethane (1 mL) was treated with cyclopropylamine (0.144 mmol) and triethylamine (0.215 mmol). After stirring at room temperature for 10 min, sodium triacetoxyborohydride (0.330 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. Trifluoroacetic acid (6.53 mmol) was added to quench the reaction. The reaction mixture was then concentrated and purified by HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(3-oxocyclobutane-1-carboxamido)pyridine-2-)-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 511.2 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.32 (s, 1H), 8.20 - 8.00 (m, 2H), 7.91 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 6.08 (d, J = 7.1 Hz, 1H), 4.00 (s, 3H), 3.98 - 3.91 (m, 1H), 3.29 - 3.17 (m, 1H), 2.75 (ddt, J = 15.7, 12.1, 8.4 Hz, 3H), 2.65 - 2.48 (m, 2H), 1.78 - 1.37 (m, 3H), 0.95 (dtt, J = 7.4, 5.2, 2.8 Hz, 2H), 0.92 - 0.84 (m, 2H). Example 68 : Synthesis of (R)-(4-(5-(3- acetamidobicyclo [1.1.1] pentane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 312) Step 1. (R)-(4-(5-(3-(( tributyloxycarbonyl ) amino ) bicyclo [1.1.1] pentane -1- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester

Prepared according to the procedure described in step 1 of Example 62, using 3-((tert-butyloxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (0.186 mmol) instead of (1r,3r)-3-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid. Step 2. 1-(2-chloropyridin-3-yl ) ethyl (R)-(4-(5-(3- aminobicyclo [1.1.1] pentane -1- carboxamido ) pyridin - 2 - yl )-1 - methyl - 1H -1,2,3- triazol - 5 - yl ) carbamate

Prepared according to the procedure described in step 2 of Example 62. Step 3. 1- (2-chloropyridin-3-yl ) ethyl (R)-(4-(5-(3- acetamidobicyclo [1.1.1] pentane -1 - carboxamido ) pyridin - 2 - yl )-1 - methyl - 1H -1,2,3 - triazol - 5 - yl ) carbamate

(R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(3-aminobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.0425 mmol) dissolved in acetonitrile was treated with triethylamine (0.287 mmol) followed by acetic anhydride (0.212 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated and purified by HPLC to give the bisacylated product. The bisacylated product was dissolved in tetrahydrofuran (2 mL) and treated with 1 N sodium hydroxide solution (800 µL). The reaction mixture was stirred at room temperature for 100 min. The reaction mixture was then concentrated and purified by HPLC to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-(3-acetamidobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 525.1 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.93 (s, 1H), 8.32 (s, 1H), 8.13 (dd, J = 8.6, 2.6 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.55 (s, 2H), 6.08 (d, J = 6.4 Hz, 1H), 3.99 (s, 3H), 2.44 (s, 6H), 1.94 (d, J = 8.8 Hz, 3H), 1.62 (s, 3H). Example 69 : Preparation of (R)-(4-(5-(1- cyanocyclopropane -1 -carboxamido )-6- methylpyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 313) Step 1 : (R)-(6-(5-(((1-(2,5 -difluoropyridin -3 -yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl )-2 -methylpyridin -3 -yl ) carbamic acid tributyl ester

4-(5-((tri-butyloxycarbonyl)amino)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (3 mmol), trimethylsilylazide (3 mmol) and T3P (50% in THF) (4.5 mmol) were dissolved in THF (20 mL). Triethylamine (6 mmol) was added dropwise at room temperature to give a clear solution after 5-30 min. (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol (4.5 mmol) was added and the reaction was heated at 80 °C for 2 h. Silica gel was then added and the crude mixture was concentrated in vacuo and then purified by column chromatography to give (R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl )carbamic acid tributyl ester (2.95 mmol). Step 2 : (R)-(4-(5- amino -6- methylpyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester hydrochloride

(R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)carbamate (2.95 mmol) was suspended in 10 mL of 4 M hydrochloric acid in dioxane for 1 h. The mixture was then concentrated in vacuo to give (R)-(4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride which was used without further purification. Step 3 : (R)-(4-(5-(1- cyanocyclopropane -1 -carboxamido )-6- methylpyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin - 3 -yl ) ethyl ester

To a mixture of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (0.127 mmol) in pyridine (1 mL) were added 1-cyanocyclopropane-1-carboxylic acid (0.254 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.139 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 483 [M+H]+). 1H NMR (400 MHz, Methanol-d4) δ 8.17 - 7.66 (m, 4H), 5.95 (s, 1H), 3.99 (s, 3H), 2.46 (s, 3H), 1.82 - 1.39 (m, 7H). Example 70 : Preparation of (R)-(1- methyl -4-(6- methyl -5-(2-( trifluoromethyl ) pyrimidine -5- carboxamido ) pyridin -2- yl )-1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 314) Step 1 : (R)-(1- methyl -4-(6- methyl -5-(2-( trifluoromethyl ) pyrimidine -5- carboxamido ) pyridin -2- yl )-1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester

To a mixture of (R)-(4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (0.127 mmol) in pyridine (0.5 mL) were added 2-(trifluoromethyl)pyrimidine-5-carboxylic acid (0.254 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.139 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 h, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(1-methyl-4-(6-methyl-5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate. LCMS (MS (m/z) 564 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.47 (s, 2H), 8.22 - 7.60 (m, 4H), 5.97 (s, 1H), 4.01 (s, 3H), 2.53 (s, 3H), 1.58 (d, J = 27.1 Hz, 3H). Example 71 : Preparation of (R)-(4-(6- fluoro -5-(6-( trifluoromethyl ) nicotinamido ) pyridin -2- yl )-1- methyl -1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 315) Step 1 : (R)-(4-(5- amino -6- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester

To a solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (1.4 mmol) in tetrahydrofuran (15 mL) at -78 °C was added a 1 M solution of lithium bis(trimethylsilyl)amide (1.4 mmol). After 15 min, a 2.5 M solution of n-butyllithium (3.5 mmol) was added. After 1 h, a 2 M solution of zinc chloride (3.5 mmol) was added and the reaction was stirred at 15 °C for 30 min. At this time, 6-bromo-2-fluoropyridin-3-amine (1.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.14 mmol) were added to the reaction and the reaction mixture was heated to 80 °C for 3 hours. After the reaction was complete, the mixture was cooled and quenched with saturated _NaHCO3 and extracted with ethyl acetate (30 mL, x2). The organics were separated, dried over sodium sulfate, and filtered through a silica plug and used in the next step without further purification. Step 2 : (R)-1-(2-chloropyridin-3-yl)ethyl(4-(6- fluoro - 5- ( 6- ( trifluoromethyl ) nicotinamido ) pyridin - 2- yl )-1- methyl -1H-1,2,3 - triazol -5 - yl ) carbamate

To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-6-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.15 mmol) in pyridine (1 mL) were added 6-(trifluoromethyl)nicotinic acid (0.3 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.3 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 h, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(6-fluoro-5-(6-(trifluoromethyl)nicotinamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 315) (MS (m/z) 565 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.31 - 9.13 (m, 1H), 8.67 - 8.43 (m, 2H), 8.43 - 8.06 (m, 2H), 8.07 - 7.80 (m, 2H), 7.49 (s, 1H), 6.12 (q, J = 6.6 Hz, 1H), 4.00 (s, 3H), 1.55 (s, 3H). Example 72 : Preparation of (R)-(4-(5-(1- cyanocyclopropane -1- carboxamido )-6- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 316)

To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-6-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.15 mmol) in pyridine (1 mL) were added 1-cyanocyclopropane-1-carboxylic acid (0.3 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.3 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(5-(1-cyanocyclopropane-1-carboxamido)-6-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 485 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.49 - 8.24 (m, 2H), 8.24 - 8.04 (m, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.68 - 7.26 (m, 1H), 6.11 (q, J = 6.7 Hz, 1H), 3.98 (s, 3H), 1.92 - 1.50 (m, 7H). Example 73 : Preparation of (R)-(4-(4- fluoro -5-(6-( trifluoromethyl ) nicotinamidyl ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 317) Step 1 : (R)-(4-(5- amino -4- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester

To a solution of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (1.4 mmol) in tetrahydrofuran (15 mL) at -78 °C was added a 1 M solution of lithium bis(trimethylsilyl)amide (1.4 mmol). After 15 min, a 2.5 M solution of n-butyllithium (3.5 mmol) was added. After 1 h, a 2 M solution of zinc chloride (3.5 mmol) was added and the reaction was stirred at 15 °C for 30 min. At this time, 6-bromo-4-fluoropyridin-3-amine (1.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.14 mmol) were added to the reaction and the reaction mixture was heated to 80 °C for 3 hours. After the reaction was complete, the mixture was cooled and quenched with saturated _NaHCO3 and extracted with ethyl acetate (30 mL, x2). The organics were separated, dried over sodium sulfate, and filtered through a silica plug and used in the next step without further purification. Step 2 : (R)-1-(2-chloropyridin-3-yl)ethyl(4-(4- fluoro - 5- ( 6- ( trifluoromethyl )nicotinamido ) pyridin - 2 - yl )-1- methyl -1H-1,2,3 - triazol -5 - yl ) carbamate

To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-6-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.15 mmol) in pyridine (1 mL) were added 6-(trifluoromethyl)nicotinic acid (0.3 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.3 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 h, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(4-fluoro-5-(6-(trifluoromethyl)nicotinamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 564.9 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.38 - 9.20 (m, 1H), 8.60 (d, J = 8.1 Hz, 1H), 8.35 - 8.26 (m, 1H), 8.07 - 7.93 (m, 2H), 7.88 (d, J = 11.3 Hz, 1H), 7.63 - 7.34 (m, 2H), 6.16 - 6.03 (m, 1H), 4.01 (s, 3H), 1.55 (s, 3H). Example 74 : Preparation of (R)-(4-(6- fluoro -5-(2-( trifluoromethyl ) pyrimidine -5- carboxamido ) pyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 318)

To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-amino-6-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.15 mmol) in pyridine (1 mL) were added 2-(trifluoromethyl)pyrimidine-5-carboxylic acid (0.3 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.3 mmol). The reaction mixture was allowed to stand with magnetic stirring for 2 h, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give 1-(2-chloropyridin-3-yl)ethyl (R)-(4-(6-fluoro-5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (MS (m/z) 566 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.46 (s, 2H), 8.57 (dd, J = 9.8, 8.2 Hz, 1H), 8.45 - 8.02 (m, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.49 (s, 1H), 6.12 (q, J = 6.5 Hz, 1H), 4.00 (s, 3H), 1.66 (s, 3H). Example 75 : Preparation of (R)-(4-(5-(6- chloronitroamino ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 319) Step 1 : (2- bromopyrimidin -5- yl ) carbamic acid tert-butyl ester

To a solution of 2-bromopyrimidin-5-amine (23 mmol) in THF (28 mL) was added tert-butyl dicarbonate (34.4 mmol). The reaction was heated to 70 °C for 16 h, followed by the addition of tert-butyl dicarbonate (18.3 mmol). The reaction was then stirred at 70 °C for 2 h. The reaction mixture was concentrated to give tert-butyl (2-bromopyrimidin-5-yl)carbamate. Step 2 : 4-(5-(( tert-butyloxycarbonyl ) amino ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid ( Intermediate 9)

To a solution of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (48.5 mmol) in tetrahydrofuran (500 mL) at −70 °C was added a 1 M solution of lithium bis(trimethylsilyl)amide (53.4 mmol). After 15 minutes, a 2.5 M solution of n-butyl lithium (101.8 mmol) was added. After 1 hour, a 2 M solution of zinc chloride (101.9 mmol) was added and the reaction was stirred at 15 °C for 30 minutes. At this point, tributyl (2-bromopyrimidin-5-yl)carbamate (29.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.85 mmol) were added to the reaction and the reaction mixture was heated to 90 °C for 16 h. After the reaction was completed, the mixture was cooled and 2 M aqueous sodium hydroxide solution (800 mL) was added. The organics were separated and the aqueous layer was extracted with methyl tert-butyl ether (500 mL×2). The organics were discarded and the aqueous layer was treated with 12 M HCl (140 mL) and petroleum ether (160 mL). The product was crushed and filtered and washed with 30:1 methyl tert-butyl ether/dichloromethane (70 mL), followed by purification by column chromatography to give 4-(5-((tert-butyloxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 9). Step 3 : (R)-(2-(5-(((1-(2,5 -difluoropyridin -3 -yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyrimidin -5- yl ) carbamic acid tributyl ester

4-(5-((tri-butyloxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 9) (0.97 mmol), trimethylsilyl azide (1.46 mmol) and T3P (50% in DMF) (1.46 mmol) were dissolved in THF (5 mL). Triethylamine (1.95 mmol) was added dropwise at room temperature. The reaction was heated to 70 °C for 50 min, then (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol (1.45 mmol) was added and the reaction was heated at 70 °C for another 6 h. The reactants were concentrated and then purified by column chromatography to obtain (R)-(2-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)carbamic acid tert-butyl ester. Step 4 : (R)-(4-(5- aminopyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester

To a solution of (R)-tributyl(2-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)carbamate (0.52 mmol) in dichloromethane (3.4 mL) was added a solution of 4 M HCl in 1,4-dioxane (3.8 mL). The reaction was stirred at room temperature for 2 h. The reaction was concentrated to give 1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as the hydrochloride salt. Step 5 : (R)-(4-(5-(6- chloronicotinamide ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester

To a mixture of (R)-(4-(5-aminopyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (0.073 mmol) in pyridine (1 mL) was added 6-chloronicotinic acid (0.082 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.087 mmol). The reaction mixture was stirred for 1 hour and then concentrated. The residue was dissolved in acetonitrile and water (2 mL) and purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(6-chloronicotinoyl)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 319). (MS (m/z) 516.0 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.19 (s, 2H), 8.98 (d, J = 2.5 Hz, 1H), 8.37 (dd, J = 8.3, 2.5 Hz, 1H), 8.04 (s, 1H), 7.71 - 7.59 (m, 2H), 5.96 (d, J = 6.2 Hz, 1H), 4.01 (s, 3H), 1.61 (s, 3H). Example 76 : Preparation of (R)-(4-(5-(6- chloronitroamino ) pyrrolidone - 2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 320) Step 1 : (5- bromopyridine - 2- yl ) carbamic acid tributyl ester

To a solution of 5-bromopyridine-2-amine (689 mmol) in DCM (840 mL) was added diisopropylethylamine (2.07 mol), DMAP (689 mmol) and tert-butyl dicarbonate (34.4 mmol) at 0°C. The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated and then purified by column chromatography to give tert-butyl (5-bromopyridine-2-yl)carbamate. Step 2 : 4-(5-(( tert-butyloxycarbonyl ) amino ) pyridine - 2- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid

To a solution of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (242 mmol) in tetrahydrofuran (2.5 L) at −70 °C was added a 1 M solution of lithium bis(trimethylsilyl)amide (266 mmol). After 15 min, a 2.5 M solution of n-butyl lithium (507.5 mmol) was added. After 1 h, a 2 M solution of zinc chloride (509.7 mmol) was added and the reaction was stirred at 15 °C for 30 min. At this point, tributyl (5-bromopyridin-2-yl)carbamate (218 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24.2 mmol) were added to the reaction and the reaction mixture was heated to 90 °C for 16 h. After the reaction was complete, the mixture was cooled and 2 M aqueous sodium hydroxide solution (1.5 L) was added. The organics were separated and the aqueous layer was extracted with methyl tert-butyl ether (2.0 L×2). The organics were discarded and the aqueous layer was treated with 12 M HCl (250 mL) and methyl tert-butyl ether (900 mL). The product was precipitated and filtered and washed with methyl tert-butyl ether (300 mL) to give 4-(5-((tert-butyloxycarbonyl)amino)pyrrolidine-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid. Step 3 : (R)-(5-(5-(((1-(2,5 -difluoropyridin -3 -yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) pyrrol - 2- yl ) carbamic acid tributyl ester

4-(5-((tri-butyloxycarbonyl)amino)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (0.62 mmol), trimethylsilyl azide (0.94 mmol) and T3P (50% in DMF) (0.94 mmol) were dissolved in THF (5 mL). Triethylamine (1.25 mmol) was added dropwise at room temperature followed by (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol (0.93 mmol). The reaction was heated at 70 °C for 6 h. The reactants were concentrated and then purified by column chromatography to give (R)-(5-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl) pyrrolidone )carbamate tert - butyl ester. Step 4 : (R)-(4-(5- aminopyrrolidone )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamate 1- (2,5 -difluoropyridin -3 -yl ) ethyl ester ( Intermediate 10)

To a solution of (R)-tributyl(5-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyrrol-2-yl)carbamate (0.52 mmol) in dichloromethane (3.4 mL) was added 4M HCl in 1,4-dioxane (3.8 mL). The reaction was stirred at room temperature for 2 h. The reaction was concentrated to give 1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyrrol-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as the hydrochloride salt (Intermediate 10). Step 5 : (R)-(4-(5-(6- chloronicotinamide ) pyrrolidone - 2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester

To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 10) (0.073 mmol) in pyridine (1 mL) was added 6-chloronicotinic acid (0.082 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.087 mmol). The reaction mixture was stirred for 1 h and then concentrated. The residue was dissolved in acetonitrile and water (2 mL) and purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(6-chloronicotinoyl)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 320). (MS (m/z) 515.9 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.44 (s, 1H), 9.01 - 8.90 (m, 2H), 8.38 (dd, J = 8.4, 2.5 Hz, 1H), 8.09 - 7.98 (m, 2H), 7.64 (dd, J = 8.3, 0.7 Hz, 1H), 5.95 (d, J = 7.0 Hz, 1H), 4.00 (s, 3H), 1.62 (s, 3H). Example 77 : Preparation of (R)-(4-(5-(6-( difluoromethyl ) nicotinoyl ) pyrrolidone -2 - yl ) -1- methyl - 1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3 - yl ) ethyl ester ( Compound 321)

The procedure described in Example 76 for the preparation of (R)-(4-(5-(6-chloronicotinamido)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester was followed using 6-(difluoromethyl)nicotinic acid (0.08 mmol) instead of 6-chloronicotinic acid to give (R)-(4-(5-(6-(difluoromethyl)nicotinamido)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester (Compound 321). (MS (m/z) 532.0 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.46 (d, J = 1.5 Hz, 1H), 9.29 - 9.16 (m, 1H), 8.97 (d, J = 1.6 Hz, 1H), 8.55 (dd, J = 8.2, 2.2 Hz, 1H), 8.05 (s, 1H), 7.93 - 7.78 (m, 2H), 6.83 (t, J = 55.0 Hz, 1H), 5.95 (d, J = 6.8 Hz, 1H), 4.00 (s, 3H), 1.62 (s, 3H). Example 78 : Preparation of (R)-(1- methyl -4-(5-(6-( trifluoromethyl ) nicotinamido ) pyrrolidone - 2- yl )-1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3 - yl ) ethyl ester ( Compound 322)

The procedure described in Example 76 for the preparation of (R)-(4-(5-(6-chloronicotinamido)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester was followed using 6-(trifluoromethyl)nicotinic acid (0.08 mmol) instead of 6-chloronicotinic acid to give (R)-(1-methyl-4-(5-(6-(trifluoromethyl)nicotinamido)pyrrolidone-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester (Compound 322). (MS (m/z) 549.9 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.49 (d, J = 20.4 Hz, 1H), 9.27 (d, J = 2.1 Hz, 1H), 8.98 (d, J = 1.5 Hz, 1H), 8.70 - 8.50 (m, 1H), 8.11 - 7.70 (m, 3H), 5.95 (d, J = 6.9 Hz, 1H), 4.00 (s, 3H), 1.63 (s, 3H). Example 79 : Preparation of (R)-(4-(5-(2,3 -difluoroisocyanatopyridin - 2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 323)

The procedure described in Example 76 for the preparation of (R)-(4-(5-(6-chloronicotinamide)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester was followed using 2,3-difluoroisonicotinic acid (0.08 mmol) instead of 6-chloronicotinic acid to give (R)-(4-(5-(2,3-difluoroisonicotinamide)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester (Compound 323). (MS (m/z) 518.0 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.41 (s, 1H), 8.96 (d, J = 1.5 Hz, 1H), 8.14 (dd, J = 5.1, 1.4 Hz, 1H), 8.05 (s, 1H), 8.00 - 7.72 (m, 1H), 7.62 (dd, J = 5.0, 4.0 Hz, 1H), 5.95 (q, J = 6.6 Hz, 1H), 4.00 (s, 3H), 1.62 (s, 3H). Example 80 : Preparation of (R)-(4-(5-(2-( difluoromethyl ) pyrimidine -5- carboxamido ) pyrrolidone -2- yl )-1- methyl - 1H -1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloropyridin -3- yl ) ethyl ester ( Compound 324)

The procedure described in Example 76 was followed using (R)-1-(2-chloropyridin-3-yl)ethan-1-ol (4.64 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol in step 3 and 2-(difluoromethyl)pyrimidine-5-carboxylic acid (0.08 The step of preparing 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-(6-chloronicotinoyl)pyrrolidinoyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate using 1-(2-(difluoromethyl)pyrimidine-5-carboxamido)pyrrolidinoyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 324) was obtained. (MS (m/z) 531.0 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.56 - 9.27 (m, 3H), 8.96 (s, 1H), 8.43 - 7.85 (m, 2H), 7.52 (s, 1H), 6.84 (t, J = 54.2 Hz, 1H), 6.07 (t, J = 6.5 Hz, 1H), 4.00 (s, 3H), 1.61 (s, 3H). Example 81 : Preparation of (R)-(1- methyl -4-(5-(2-( trifluoromethyl ) pyrimidine -5- carboxamido ) pyrrolidone -2- yl )-1H-1,2,3- triazol - 5- yl ) carbamic acid 1-(2- fluoropyridin -3- yl ) ethyl ester ( Compound 325)

The procedure described in Example 76 was followed using (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (4.64 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol in step 3 and 2-(trifluoromethyl)pyrimidine-5-carboxylic acid (0.08 The step of preparing 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-(6-chloronicotinoyl)pyrrolidinoyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate using 2-(4-(5-(6-chloronicotinoyl)pyrrolidinoyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 325) was obtained. (MS (m/z) 532.9 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.49 (s, 2H), 9.45 (s, 1H), 8.97 (d, J = 1.6 Hz, 1H), 8.23 - 7.85 (m, 2H), 7.41 (s, 1H), 5.99 (q, J = 6.7 Hz, 1H), 3.99 (s, 3H), 1.63 (s, 3H). Example 82 : Preparation of (R)-(1- methyl -4-(5-(6-( trifluoromethyl ) nicotinoyl ) pyrrolidone - 2 -yl )-1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- fluoropyridin -3- yl ) ethyl ester ( Compound 326)

The procedure described in Example 76 was followed with the use of (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (4.64 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol in step 3 and 6-(trifluoromethyl)nicotinic acid (0.08 The step of preparing 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-(6-chloronicotinoyl)pyrrolidone)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate using 2-(4-(5-(6-(trifluoromethyl)nicotinoyl)pyrrolidone)-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 326) was obtained. (MS (m/z) 532.0 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.47 (s, 1H), 9.28 (d, J = 2.1 Hz, 1H), 8.97 (d, J = 1.5 Hz, 1H), 8.60 (dd, J = 8.3, 2.1 Hz, 1H), 8.25 - 8.06 (m, 2H), 8.01 (dd, J = 8.2, 0.8 Hz, 1H), 7.41 (s, 1H), 5.99 (q, J = 6.6 Hz, 1H), 3.99 (s, 3H), 1.63 (s, 3H). Example 83 : Preparation of (R)-(4-(5-(2-( difluoromethyl ) pyrimidine -5- carboxamido ) pyrrolidone -2- yl )-1- methyl - 1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- fluoropyridin -3- yl ) ethyl ester ( Compound 327)

The procedure described in Example 76 was followed using (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (4.64 mmol) instead of (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol in step 3 and 2-(difluoromethyl)pyrimidine-5-carboxylic acid (0.08 The step of preparing 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-(6-chloronicotinoyl)pyrrolidinoyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate using 1-(2,5-difluoropyridin-3-yl)ethyl (R)-(4-(5-(2-(difluoromethyl)pyrimidine-5-carboxamido)pyrrolidinoyl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 327) was obtained. (MS (m/z) 514.9 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.62 - 9.34 (m, 3H), 8.97 (s, 1H), 8.30 - 7.93 (m, 2H), 7.41 (s, 1H), 6.84 (t, J = 54.1 Hz, 1H), 5.99 (d, J = 7.2 Hz, 1H), 3.99 (s, 3H), 1.63 (s, 3H). Example 84 : Preparation of (R)-(4-(5-(1- cyanocyclopropane -1 - carboxamido ) pyrrolidone - 2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 328)

To a mixture of (R)-(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 10) (0.049 mmol), 1-cyanocyclopropanecarboxylic acid (0.058 mmol) and (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-N-oxo-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1 The reaction was stirred for 48 hours, then concentrated and purified by reverse phase HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 328) (MS (m/z) 470.0 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.22 (s, 1H), 8.96 (d, J = 1.5 Hz, 1H), 8.11 - 7.67 (m, 2H), 5.95 (d, J = 6.8 Hz, 1H), 4.01 (s, 3H), 1.88 - 1.80 (m, 2H), 1.80 - 1.72 (m, 2H), 1.62 (s, 3H). Example 85 : Preparation of Compounds 286-287 and 329-332

Compounds 286-287 and 329-332 were generally synthesized according to Scheme C. For example, (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 329) was prepared as follows. Preparation of (R)-1- (2 - chloro - 5- fluoropyridin - 3- yl ) ethyl (4-(5-(1- cyanocyclopropane -1- carboxamido ) pyrimidin - 2 - yl )-1- methyl -1H-1,2,3 - triazol -5- yl ) carbamate ( Compound 329) Step 1 : (R)-(4-(5-(( tributyloxycarbonyl ) amino ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin - 3- yl ) ethyl ester

To a mixture of 4-(5-((tributyloxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 9) (0.62 mmol) in THF (5 mL) was added T3P (50% in DMF, 0.94 mmol), TMS-N3 (0.67 mmol) and triethylamine (1.2 mmol). The mixture was heated at 70 °C for 30 min. (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethan-1-ol (0.94 mmol) was added and the solution was heated at 70 °C for 90 min. The reaction was cooled to room temperature, concentrated and purified by silica gel chromatography to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-((tributyloxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5- yl )carbamate. (MS ( m/z ) 493.2 [M+H] ⁺ ). Step 2 : (R)-1-(2- chloro -5- fluoropyridin - 3- yl ) ethyl (4-(5- aminopyrimidin - 2-yl )-1- methyl -1H-1,2,3 - triazol -5- yl ) carbamate ( Intermediate 11)

4 M HCl in 1,4-dioxane (20 mmol) was added to (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-((tributyloxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.49 mmol). The resulting suspension was stirred at room temperature for 18 h. The reactant was concentrated to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-aminopyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 11) as a hydrochloride salt. (MS ( m/z ) 393.1 [M+H] ⁺ ). Step 3 : (R)-(4-(5-(1 -cyanocyclopropane -1 -carboxamido ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin -3- yl ) ethyl ester

A vial was charged with (R)-ethyl (4-(5-aminopyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate 1-(2-chloro-5-fluoropyridin-3-yl) hydrochloride (0.05 mmol) (intermediate 11), 1-cyanocyclopropane-1-carboxylic acid (0.06 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.07 mmol) and pyridine (2 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated and purified by reverse phase HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS ( m/z ) 486.2 [M+H] ⁺ ). 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.98 (bs, 1H), 8.99 (s, 2H), 8.43 (bs, 1H), 7.94 (bs, 1H), 5.82 (bs, 1H), 3.91 (s, 3H), 1.84 - 1.68 (m, 4H), 1.55 (bs, 3H).

Compounds 286-287 and 329-332 (Table 5) were prepared similarly according to Scheme C, Step 4, by reacting (R)-(4-(5-aminopyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester hydrochloride (Intermediate 11) with the reagent rings listed in Table 4 instead of 1-cyanocyclopropane-1-carboxylic acid.

Compounds 286-287 were prepared using a mixture of (1S,2S)-1-cyano-2-(difluoromethyl)cyclopropane-1-carboxylic acid and (1R,2R)-1-cyano-2-(difluoromethyl)cyclopropane-1-carboxylic acid, followed by chiral SFC purification. Table 5 : Compounds prepared according to Scheme C. Compound No. Structure Reagent LCMS m/z 1H NMR Compound 286 (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-((1R,2R)-1-cyano-2-(difluoromethyl)cyclopropane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. 536.0 1H NMR (400 MHz, DMSO-d6) δ 10.67 (bs, 1H), 9.99 (bs, 1H), 8.98 (s, 2H), 8.44 (bs, 1H), 7.94 (bs, 1H), 6.23 (ddd, J = 55.6, 54.3, 5.3 Hz, 1H), 5.83 (bs, 1H), 3.91 (s, 3H), 2.82 - 2.58 (m, 1H), 2.20-2.11 (m, 1H), 2.11-2.00 (m, 1H), 1.54 (bs, 3H). Compound 287 (R)-(4-(5-((1S,2S)-1-cyano-2-(difluoromethyl)cyclopropane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester 536.0 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.98 (bs, 1H), 8.99 (s, 2H), 8.44 (s, 1H), 7.94 (bs, 1H), 6.23 (ddd, J = 55.6, 54.3, 5.3 Hz, 1H), 5.83 (bs, 1H), 3.92 (s, 3H), 2.81 - 2.59 (m, 1H), 2.19-2.11 (m, 1H), 2.11-2.02 (m, 1H), 1.54 (m, 3H). Compound 329 (R)-(4-(5-(1-cyanocyclopropane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester 486.2 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.98 (bs, 1H), 8.99 (s, 2H), 8.43 (bs, 1H), 7.94 (bs, 1H), 5.82 (bs, 1H), 3.91 (s, 3H), 1.84 - 1.68 (m, 4H), 1.55 (bs, 3H). Compound 330 (R)-(4-(5-(3-fluorobicyclo[1.1.1]pentane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester 505.2 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.91 (bs, 1H), 9.02 (s, 2H), 8.43 (bs, 1H), 7.94 (bs, 1H), 5.82 (bs, 1H), 3.91 (s, 3H), 2.45 (d, J = 2.5 Hz, 6H), 1.54 (bs, 3H). Compound 331 (R)-(1-methyl-4-(5-((1R,2R)-2-(trifluoromethyl)cyclopropane-1-carboxamido)pyrimidin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester 529.0 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.86 (bs, 1H), 8.97 (s, 2H), 8.42 (bs, 1H), 7.93 (bs, 1H), 5.79 (bs, 1H), 3.91 (s, 3H), 2.45 - 2.23 (m, 2H), 1.85 - 0.97 (m, 5H). Compound 332 (R)-(1-methyl-4-(5-(6-(trifluoromethyl)nicotinamido)pyrimidin-2-yl)-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester 566.0 1H NMR (400 MHz, DMSO-d6) δ 11.05 (bs, 1H), 10.01 (bs, 1H), 9.31 (d, J = 2.2 Hz, 1H), 9.16 (s, 2H), 8.63 (dd, J = 8.1, 2.2 Hz, 1H), 8.44 (bs, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.94 (bs, 1H), 5.85 (d, J = 7.5 Hz, 1H), 3.93 (s, 3H), 1.54 (bs, 3H). Example 86 : Preparation of (R)-(4-(5-(3- fluorobicyclo[1.1.1]pentane-1-carboxamido)pyrrolidone - 2 - yl ) -1 - methyl - 1H - 1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin -3- yl ) ethyl ester ( Compound 333) Step 1 : (R)-(4-(5-(( tributyloxycarbonyl ) amino ) pyrrolidone -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin -3- yl ) ethyl ester

To a mixture of 4-(5-((tert-butoxycarbonyl)amino)pyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (0.62 mmol) in THF (5 mL) was added T3P (50% in DMF, 0.94 mmol), TMS-N3 (0.69 mmol) and triethylamine (1.2 mmol). The mixture was heated at 70 °C for 30 min. (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethan-1-ol (0.94 mmol) was added and the solution was heated at 70 °C for 90 min. The reaction was cooled to room temperature, concentrated and purified by silica gel chromatography to give (R)-(4-(5-((tributyloxycarbonyl)amino)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2-chloro-5-fluoropyridin-3-yl)ethyl ester. (MS ( m/z ) 492.9. [M+H] ⁺ ). Step 2 : (R)-(4-(5- aminopyrrolidone - 2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2- chloro -5- fluoropyridin -3- yl ) ethyl ester

4 M HCl in 1,4-dioxane (14 mmol) was added to 1-(2-chloro-5-fluoropyridin-3-yl)ethyl (R)-(4-(5-((tributyloxycarbonyl)amino)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (0.34 mmol). The resulting suspension was stirred at room temperature for 18 hours. The reaction was concentrated to give 1-(2-chloro-5-fluoropyridin-3-yl)ethyl (R)-(4-(5-aminopyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate as a hydrochloride salt. Step 3 : (R) -1-(2- chloro-5 - fluoropyridin -3- yl ) ethyl (4-(5-(3- fluorobicyclo [1.1.1] pentane - 1 - carboxamido ) pyrrolidone -2- yl ) -1- methyl -1H-1,2,3 - triazol - 5 - yl ) carbamate

A vial was charged with (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-aminopyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (0.06 mmol), 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (0.08 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12 mmol), and pyridine (2 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated and purified by reverse phase HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(4-(5-(3-fluorobicyclo[1.1.1]pentane-1-carboxamido)pyrrolidone-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS ( m/z ) 505.2 [M+H] ⁺ ). 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.03 (bs, 1H), 9.20 (d, J = 1.6 Hz, 1H), 8.92 (d, J = 1.5 Hz, 1H), 8.43 (bs, 1H), 7.94 (bs, 1H), 5.83 (bs, 1H), 3.92 (s, 3H), 2.47 (d, J = 2.5 Hz, 6H), 1.55 (bs, 3H). Example 87 : Preparation of (R)-(4-(5-((1r,3R)-3- cyano -3- methoxycyclobutane -1 - carboxamido ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 334) and (R)-(4-(5-((1s,3S)-3- cyano -3- methoxycyclobutane -1 -carboxamido ) pyrimidin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3 -yl ) ethyl ester ( Compound 335)

A mixture of (R)-(4-(5-aminopyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester hydrochloride (0.048 mmol), 3-cyano-3-methoxycyclobutane-1-carboxylic acid (2 equiv.), EDCI (2 equiv.) in pyridine (1 mL) was stirred at room temperature for 1 hour. After the reaction was completed, the residue was purified by preparative HPLC using Gilson preparative HPLC (Gemini column, 30%-95% CH ₃ CN in H ₂ O and 0.1% TFA). Two peaks were separated; the stereostructure was assigned arbitrarily. Compound 334: (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-((1r,3R)-3-cyano-3-methoxycyclobutane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 514.1 [M+H]+). 1H NMR (400 MHz, Methanol-d4) δ 9.06 (s, 2H), 8.07 (m, 1H), 7.98 - 7.69 (m, 1H), 5.96 (m, 1H), 4.02 (s, 3H), 3.46 (s, 2H) 2.99 - 2.79 (m, 2H), 2.76 - 2.48 (m, 2H), 1.63 (s, 3H). Compound 335: (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-((1s,3S)-3-cyano-3-methoxycyclobutane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 514.1 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 9.05 (s, 2H), 8.05 (s, 1H), 7.97 - 7.75 (m, 1H), 5.96 (m, 1H), 4.01 (s, 3H), 3.55 - 3.49 (m, 1H), 2.85 (m, 2H), 2.66 (m, 2H), 1.63 (s, 3H). Example 88 : Preparation of (R)-(4-(5-(1- cyanocyclopropane -1 -carboxamido )-3- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 336) Step 1 : (6- bromo -5- fluoropyridin -3- yl ) carbamic acid tert-butyl ester

To a solution of 6-bromo-5-fluoropyridin-3-amine (2.8 mmol) in THF (20 mL) was added tributyl dicarbonate (5.7 mmol). The reaction was heated to 70 °C for 16 h and filtered through a silica plug to afford the title compound which was used in the next step without further purification. Step 2 : 4-(5-(( tributyloxycarbonyl ) amino )-3- fluoropyridin -2- yl )-1- methyl -1H-1,2,3 - triazole -5-carboxylic acid

To a solution of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (1.3 mmol) in tetrahydrofuran (20 mL) was added 1 M solution of lithium bis(trimethylsilyl)amide (1.5 mmol) at -70 °C. After 15 minutes, 2.5 M solution of n-butyl lithium (2.5 mmol) was added. After 1 hour, 2 M solution of zinc chloride (2.5 mmol) was added and the reaction was stirred at 15 °C for 30 minutes. At this point, tributyl (6-bromo-5-fluoropyridin-3-yl)carbamate (1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.08 mmol) were added to the reaction and the reaction mixture was heated to 90 °C for 3 hours. After the reaction was completed, the reactants were cooled and diluted with 1 M aqueous hydrogen chloride solution (20 mL). The reaction mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate, concentrated, and purified by column chromatography to obtain 4-(5-((tri-butyloxycarbonyl)amino)-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid. Step 3 : (R)-(6-(5-(((1-(2,5 -difluoropyridin -3 -yl ) ethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl )-5- fluoropyridin -3- yl ) carbamic acid tributyl ester

4-(5-((tri-butyloxycarbonyl)amino)-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (3.1 mmol), trimethylsilylazide (4.7 mmol) and T3P (50% in DMF) (4.7 mmol) were dissolved in THF (5 mL). Triethylamine (9.4 mmol) was added dropwise at room temperature to give a clear solution after 5-30 minutes. (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol (9.4 mmol) was added and the reaction was heated at 80 °C for 2 hours. Silica gel was then added and the crude mixture was concentrated in vacuo and then purified by column chromatography to give (R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-5-fluoropyridin-3-yl)carbamic acid tert-butyl ester (0.6 mmol). Step 4 : (R)-(4-(5- amino -3- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester hydrochloride ( Intermediate 12)

(R)-tributyl(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-5-fluoropyridin-3-yl)carbamate (0.6 mmol) was suspended in 1.6 mL of 4 M hydrochloric acid in dioxane for 1 h. The mixture was then concentrated in vacuo to give 1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-amino-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 12) and used without further purification. Step 5 : (R)-(4-(5-(1 -cyanocyclopropane -1 -carboxamido )-3- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin - 3- yl ) ethyl ester

To a mixture of (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-amino-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (0.07 mmol) in pyridine (1 mL) were added 1-cyanocyclopropane-1-carboxylic acid (0.07 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.08 mmol). The reaction mixture was allowed to stand under magnetic stirring for 2 hours, at which time water (1 mL) was added and the crude mixture was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(1-cyanocyclopropane-1-carboxamido)-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 486.986 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.78 - 8.52 (m, 1H), 8.19 - 7.53 (m, 3H), 5.90 (d, J = 6.8 Hz, 1H), 4.02 (s, 3H), 1.91 - 1.35 (m, 7H). Example 89 : Preparation of (R)-(4-(5-(3- cyanobicyclo [1.1.1] pentane -1- carboxamido )-3- fluoropyridin -2 -yl )-1- methyl -1H-1,2,3 - triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3 -yl ) ethyl ester ( Compound 337) (R)-1-( 2,5 -difluoropyridin - 3-yl ) ethyl (4-(5-(3- cyanobicyclo [1.1.1] pentane -1 - carboxamido )-3- fluoropyridin -2 - yl )-1- methyl -1H-1,2,3 - triazol -5 - yl ) carbamate

Example 88 was followed using 3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid (0.07 mmol) instead of 1-cyanocyclopropane-1-carboxylic acid to prepare (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid amido)-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate. (MS (m/z) 513.010 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.61 (s, 1H), 8.25 - 7.51 (m, 3H), 5.89 (d, J = 7.0 Hz, 1H), 4.01 (s, 3H), 2.64 (s, 6H), 1.61 (s, 3H). Example 90 : Preparation of (R)-(4-(5-(6- chloronitroamino )-3- fluoropyridin -2- yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamic acid 1-(2,5 -difluoropyridin -3- yl ) ethyl ester ( Compound 338) (R)-1-(2,5 -difluoropyridin -3 -yl )(4-(5-(6- chloronicotinamide )-3 - fluoropyridin -2 - yl )-1- methyl -1H-1,2,3- triazol -5- yl ) carbamate

Example 88 was followed using 6-chloronicotinic acid (0.07 mmol) instead of 1-cyanocyclopropane-1-carboxylic acid to prepare (R)-(4-(5-(6-chloro-nicotinamido)-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid 1-(2,5-difluoropyridin-3-yl)ethyl ester. (MS (m/z) 532.975 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 8.98 (dd, J = 2.5, 0.7 Hz, 1H), 8.73 (s, 1H), 8.38 (dd, J = 8.4, 2.5 Hz, 1H), 8.27 (dd, J = 12.4, 2.1 Hz, 1H), 7.96 (d, J = 78.6 Hz, 2H), 7.66 (dd, J = 8.3, 0.8 Hz, 1H), 5.91 (d, J = 6.8 Hz, 1H), 4.03 (s, 3H), 1.62 (s, 3H). Example 91 : Preparation of rac- (1R,2R)-1- cyano -2-( difluoromethyl ) cyclopropane -1- carboxylic acid Step 1 : (3,3 -difluoroallyl )( phenyl ) sulfane

NaH (153 mmol) was added to a 250 mL bottle under _N2 . n-Hexane (50.0 mL) was added and stirred at 25°C for 5 minutes. n-Hexane was removed by syringe. Dioxane (120 mL) was added to the reaction at 0°C. PhSH (118 mmol) was added to the mixture and stirred at 0°C for 0.5 hours. 3-Bromo-3,3-difluoroprop-1-ene (177 mmol) was added to the mixture at 0°C. The reaction was warmed to 25°C and stirred at 25°C for 1 hour. The reaction was quenched with saturated _NH4Cl (50.0 mL) at 0°C and extracted with ethyl acetate (100 mL * 4). The organic phase was washed with brine (100 mL) and dried over _{anhydrous Na2SO4} . The solution was filtered and concentrated in vacuo. The residue was purified by column chromatography to give (3,3-difluoroallyl)(phenyl)sulfane. Step 2 : (E)-(3,3 -difluoroprop -1- en -1- yl )( phenyl ) sulfane

(3,3-Difluoroallyl)(phenyl)sulfane (53.7 mmol) was dissolved in DMSO (20.0 mL) in a 100 mL bottle. t-BuOK (2.68 mmol) was added to the mixture at 10°C. The mixture was warmed to 25°C and stirred at 25°C for 1 hour. The reaction was quenched by adding H ₂ O (200 mL) at 0-10°C. n-Hexane (100 mL) was added to the mixture, and the reaction was extracted with n-hexane (200 mL * 5). The combined organic phases were washed with brine (100 mL) and dried over anhydrous Na ₂ SO _4. Filtered and concentrated under vacuum to give (E)-(3,3-difluoroprop-1-en-1-yl)(phenyl)sulfane. Step 3 : (E)-(3,3 -difluoroprop- 1- en -1 -yl ) diphenyltrifluoromethanesulfonate

Diphenyliodonium trifluoromethanesulfonate (48.8 mmol) was added to a 250 mL bottle, and DCE (60.0 mL) was added. (E)-(3,3-difluoroprop-1-en-1-yl)(phenyl)sulfane (51.3 mmol) was added, followed by Cu powder (244 mmol) at 10°C. The reaction was stirred at 10-25°C for 0.5 hours, then immersed in a preheated oil bath (80°C), and stirred for 2 hours. The reaction was cooled to 20°C and then filtered through a celite pad and washed with DCM (80 mL * 4). The filtrate was concentrated and purified by column chromatography (SiO2, DCM/acetone = 100/1 to 20/1, Rf = 0.50) to obtain (E)-(3,3-difluoroprop-1-en-1-yl)trifluoromethanesulfonate diphenylphosphine. Step 4 : 2-(1R,2R)-1- cyano -2-( difluoromethyl ) cyclopropane -1- carboxylic acid ethoxyethyl ester

2-Ethoxyethyl 2-cyanoacetate (63.6 mmol) was added to a 250 mL bottle in acetone (100 mL) at 25°C. K ₂ CO ₃ (191 mmol) was added, followed by (E)-(3,3-difluoroprop-1-en-1-yl)trifluoromethanesulfonate (70.0 mmol) at 25°C and stirred for 1 hour. The reaction was filtered through a diatomaceous earth pad and washed with DCM (100 ml * 3). The organic phase was concentrated under vacuum and purified by HPLC (column: Phenomenex luna C18 (250*70 mm, 15 μm); mobile phase: [water (0.1% TFA)-ACN]; B%: 25ACN%-55ACN%, 25 min). The product fraction was adjusted to pH = 6-7 with saturated NaHCO _3. The fraction was concentrated under reduced pressure to remove ACN, then extracted with ethyl acetate (200 mL * 3), and dried over anhydrous Na ₂ SO _4. Filtered and concentrated under vacuum to obtain a crude product, which was further purified and concentrated by preparative HPLC (column: Welch Ultimate XB-CN 250*70*10 μm; mobile phase: [hexane-EtOH (0.1% NH ₃ .H ₂ O)]; B%: 1%-40%, 15 min) to obtain racemic-2-(1R,2R)-1-cyano-2-(difluoromethyl)cyclopropane-1-carboxylic acid ethoxyethyl ester. Step 5 : Racemic- (1R,2R)-1- cyano -2-( difluoromethyl ) cyclopropane -1- carboxylic acid

Racemic-2-(1R,2R)-1-cyano-2-(difluoromethyl)cyclopropane-1-carboxylic acid ethoxyethyl ester (34.3 mmol) was added to a 100 mL bottle and suspended in THF (70.0 mL). LiOH.H ₂ O (2 M, 34.30 mL) was added to the mixture at 10° C. and stirred at 10-25° C. for 3 hours. The pH was adjusted to 2 with HCl (1 N). The reactant was extracted with ethyl acetate (50.0 mL * 6) and washed with brine (50.0 mL). The organics were dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The product was triturated with DCM (20.0 mL) and the precipitate was collected by vacuum filtration to give rac-(1R,2R)-1-cyano-2-(difluoromethyl)cyclopropane-1-carboxylic acid. Example 92 : Preparation of rac- (1S,2S)-1- cyano -2- fluorocyclopropane -1- carboxylic acid Step 1 : Trimethyl ( ( phenylthio ) ethynyl ) silane

Ethylenetrimethylsilane (1.43 mol) in THF (1000 mL) was added dropwise to nBuLi (2.5 M, 570 mL, 1.43 mol) at -78°C. The reaction was stirred at -78°C for 30 minutes, and then a solution of 1,2-diphenyldisulfane (1.43 mol) in THF (400 mL) was added dropwise at -78°C. After stirring at -78°C for 30 minutes, the reaction was warmed to 15°C and stirred for 5 hours. The reaction was cooled to 0°C and H ₂ O (500 mL) was added dropwise at 0°C. The reaction was extracted with EtOAc (500 mL *2), and the aqueous layer was poured into NaClO. The combined organic layers were washed with 0.1 M NaOH (500 mL *3), H ₂ O (500 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was used directly in the next step without purification to obtain trimethyl((phenylthio)ethynyl)silane. Step 2 : Ethynyl ( phenyl ) sulfane

Trimethyl((phenylthio)ethynyl)silane (1.28 mol) was added to MeOH (2000 mL). A mixture of K ₂ CO ₃ (2.56 mol) in H ₂ O (600 mL) was added dropwise at 15° C. and stirred for 16 hours. After concentration to remove MeOH, EtOAc (400 mL) and H ₂ O (200 mL) were added. The aqueous layer was separated and extracted with EtOAc (200 mL *2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography to obtain ethynyl(phenyl)sulfane. Step 3 : (1- fluorovinyl )( phenyl ) sulfane

Ethynyl(phenyl)sulfane (1.16 mol), Pyr. (3.31 mol) were added to DCM (1000 mL). HF/Pyr. (4.62 mol) was added at 0°C, and then the reaction was warmed to 15°C and stirred for 10 minutes. Saturated NaHCO ₃ and NaHCO ₃ solid were slowly added to adjust pH=8. The organic layer was separated, washed with brine (1000 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography to give (1-fluorovinyl)(phenyl)sulfane. Step 4 : (1- fluorovinyl ) diphenylphosphine trifluoromethanesulfonate

(1-Fluorovinyl)(phenyl)sulfane (272 mmol) was suspended in DCE (400 mL). Diphenyliodonium triflate (258 mmol) and Cu (1.36 mol) were added at 15 °C. The reaction was heated to 100 °C and stirred for 30 minutes. The reaction was cooled to 15 °C, filtered and the filter cake was washed with DCM (100 mL). The filtrate was concentrated in vacuo and the residue was purified by column chromatography to give diphenylstennium (1-fluorovinyl)triflate. Step 5 : rac- (1S,2S)-1- cyano -2- fluorocyclopropane -1- carboxylic acid ethyl ester

Ethyl 2-cyanoacetate (78.8 mmol) was added to MeCN (180 mL). DBU (94.6 mmol) was added at 15 °C and stirred for 10 min, followed by the addition of (1-fluorovinyl)diphenylphosphine trifluoromethanesulfonate (78.8 mmol) portionwise at 15 °C. After stirring at 15 °C for 30 min, the reaction was quenched by the addition of saturated NH ₄ Cl (50 mL). The mixture was extracted twice with ethyl acetate (100 mL) and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography to obtain rac-(1S,2S)-1-cyano-2-fluorocyclopropane-1-carboxylic acid ethyl ester. Step 6 : rac- (1S,2S)-1- cyano -2- fluorocyclopropane -1- carboxylic acid ethyl ester

Racemic-(1S,2S)-1-cyano-2-fluorocyclopropane-1-carboxylic acid ethyl ester (14.0 mmol) was suspended in MeCN (11.0 mL) and H ₂ O (2.00 mL). Triazabicyclodecene (29.4 mmol) was added at 15°C and stirred for 1 hour. The reactant was extracted with DCM (20 mL), and the pH of the aqueous layer was adjusted to 1-3 by HCl (4 M). The aqueous layer was extracted with EtOAc (20 mL *3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography to give racemic-(1S,2S)-1-cyano-2-fluorocyclopropane-1-carboxylic acid. Example 93 : Calcium Analysis

In vitro LPAR1 activity was measured in an intracellular calcium mobilization assay.

CHO-K1 EDG2 cells (DiscoverX catalog # 93-0644C2) expressing human LPAR1 (NM_001401.3) were seeded in a total volume of 25 μL of Dulbecco's Modification of Eagle's Medium (DMEM) with 10% fetal bovine serum, 1x PenStrepGlutamine, 300 μg/ml hygromycin and 800 μg/ml G418 at 15,000 cells/well in 384-well tissue culture plates (Grenier # 781091) and incubated overnight at 37°C. Prior to the assay, 25 μL of calcium loading dye component A (FLIPR Calcium 6 Assay Kit Molecular Devices #R8190) and 2.5 mM probenecid (Invitrogen #P36400, prepared fresh) in Hank's balanced salt solution (Corning #21-023-CV), 20 mM HEPES (Corning #25-060-CI), 0.1% bovine serum albumin (Sigma-Aldrich #A7906-500G) were added to the cells for 60 min at 37°C.

Agonist dosing curves for LPA 18:2 (Avanti Polar Lipids Catalog #857138, 0.5 nM to 10 μM) were recorded to determine the LPA 18:2 _EC80 for subsequent antagonist analysis. For agonist dosing curves, cells were removed from the incubator 2 hours after dye loading and transferred to a FLIPR Tetra instrument (Molecular Devices, San Jose, CA). Calcium mobilization was monitored for 5 minutes and 10 μL of 6X LPA in HBSS/20 mM Hepes/0.1% bovine serum albumin (BSA) was added to the cells under analysis for 5 seconds.

To determine the LPAR1 antagonist activity of test compounds, cells were pre-incubated with test compounds at doses ranging from 0.5 nM to 10 μM, followed by LPA at the EC ₈₀ concentration (100 nM). After dye loading, cells were removed from the incubator and 0.3 μL of 200X antagonist was added. Cells were incubated at 37°C for 60 minutes. Antagonist activity was measured on the FLIPR Tetra. Calcium mobilization was monitored for 3.5 minutes and 10 μL of 6X EC ₈₀ LPA in HBSS, 20 mM HEPES, and 0.1% BSA was added to the cells under analysis for 5 seconds. _EC50 values were determined by plotting signal amplitude (maximum minus minimum) against _log10 of antagonist concentration using the dose response tool (Gilead Sciences Inc.).

To analyze the antagonist potential of the exemplified compounds, the EC ₅₀ values of compounds 1 to 338 were determined in the LPAR1 calcium mobilization assay. The results are shown in Table 6 (LPAR1 EC ₅₀ ). The compound numbers correspond to the compound numbers in Examples 1 to 92. N/A = not available. Table 6 Compound LPAR1 (EC ₅₀ ; Nm) Compound 1 6519.3 Compound 2 953.0 Compound 3 10000 Compound 4 10000 Compound 5 1505.8 Compound 6 1859.6 Compound 7 315.1 Compound 8 154.3 Compound 9 2696.7 Compound 10 1024.1 Compound 11 731.2 Compound 12 540.8 Compound 13 148.1 Compound 14 1202.9 Compound 15 452.1 Compound 16 2185.0 Compound 17 29.3 Compound 18 1129.3 Compound 19 275.5 Compound 20 N/A Compound 21 39.6 Compound 22 43.4 Compound 23 1105.0 Compound 24 N/A Compound 25 2268.3 Compound 26 587.4 Compound 27 1277.1 Compound 28 29.1 Compound 29 261.4 Compound 30 516.2 Compound 31 2334.4 Compound 32 798.9 Compound 33 1018.3 Compound 34 428.9 Compound 35 103.1 Compound 36 112.4 Compound 37 54.6 Compound 38 10000 Compound 39 50.8 Compound 40 75.2 Compound 41 38.1 Compound 42 201.1 Compound 43 497.2 Compound 44 165.0 Compound 45 40.8 Compound 46 29.7 Compound 47 19.1 Compound 48 22.8 Compound 49 353.2 Compound 50 1761.4 Compound 51 88.7 Compound 52 621.9 Compound 53 1456.0 Compound 54 7863.3 Compound 55 477.7 Compound 56 1135.1 Compound 57 339.2 Compound 58 205.2 Compound 59 263.7 Compound 60 140.4 Compound 61 134.4 Compound 62 109.8 Compound 63 120.4 Compound 64 76.4 Compound 65 81.9 Compound 66 66.6 Compound 67 30.8 Compound 68 40.8 Compound 69 53.0 Compound 70 47.8 Compound 71 89.7 Compound 72 17.0 Compound 73 17.3 Compound 74 1344.4 Compound 75 23.4 Compound 76 274.7 Compound 77 25.5 Compound 78 83.6 Compound 79 16.0 Compound 80 109.1 Compound 81 22.8 Compound 82 20.4 Compound 83 343.7 Compound 84 14.5 Compound 85 11.2 Compound 86 16.6 Compound 87 16.1 Compound 88 8.6 Compound 89 312.3 Compound 90 73.5 Compound 91 187.0 Compound 92 601.4 Compound 93 133.0 Compound 94 4817.8 Compound 95 308.6 Compound 96 2328.6 Compound 97 395.4 Compound 98 720.5 Compound 99 53.9 Compound 100 90.8 Compound 101 1041.5 Compound 102 85.6 Compound 103 16.6 Compound 104 559.9 Compound 105 1582.1 Compound 106 1758.3 Compound 107 10000 Compound 108 419.6 Compound 109 1711.0 Compound 110 68.2 Compound 111 190.9 Compound 112 1405.0 Compound 113 775.1 Compound 114 504.4 Compound 115 654.2 Compound 116 322.5 Compound 117 1143.9 Compound 118 1336.6 Compound 119 49.9 Compound 120 2466.1 Compound 121 264.1 Compound 122 122.9 Compound 123 625.6 Compound 124 3629.6 Compound 125 2711.3 Compound 126 1826.3 Compound 127 415.7 Compound 128 309.4 Compound 129 492.5 Compound 130 271.3 Compound 131 260.4 Compound 132 196.9 Compound 133 343.9 Compound 134 448.9 Compound 135 725.7 Compound 136 602.5 Compound 137 1092.3 Compound 138 84.9 Compound 139 123.2 Compound 140 349.3 Compound 141 459.3 Compound 142 217.4 Compound 143 188.7 Compound 144 36.1 Compound 145 184.0 Compound 146 271.0 Compound 147 33.9 Compound 148 30.4 Compound 149 328.7 Compound 150 879.5 Compound 151 3151.9 Compound 152 3987.9 Compound 153 932.6 Compound 154 667.8 Compound 155 748.4 Compound 156 50.7 Compound 157 74.5 Compound 158 117.1 Compound 159 393.6 Compound 160 1454.9 Compound 161 66.8 Compound 162 84.7 Compound 163 32.6 Compound 164 245.0 Compound 165 487.1 Compound 166 238.5 Compound 167 99.4 Compound 168 16.2 Compound 169 190.6 Compound 170 31.8 Compound 171 140.5 Compound 172 236.1 Compound 173 181.0 Compound 174 106.6 Compound 175 35.4 Compound 176 253.3 Compound 177 48.3 Compound 178 140.1 Compound 179 46.5 Compound 180 122.7 Compound 181 428.4 Compound 182 2046.8 Compound 183 1059.1 Compound 184 81.8 Compound 185 1704.2 Compound 186 100.5 Compound 187 1236.1 Compound 188 451.9 Compound 189 989.3 Compound 190 359.3 Compound 191 620.2 Compound 192 10000 Compound 193 287.1 Compound 194 832.3 Compound 195 1538.5 Compound 196 1029.5 Compound 197 5.2 Compound 198 613.1 Compound 199 65.7 Compound 200 94.0 Compound 201 145.8 Compound 202 5.0 Compound 203 94.8 Compound 204 132.2 Compound 205 8.3 Compound 206 71.8 Compound 207 41.2 Compound 208 21.1 Compound 209 17.7 Compound 210 243.2 Compound 211 37.4 Compound 212 56.4 Compound 213 175.3 Compound 214 356.8 Compound 215 1995.6 Compound 216 22.4 Compound 217 58.1 Compound 218 24.0 Compound 219 37.7 Compound 220 157.5 Compound 221 374.3 Compound 222 41.7 Compound 223 118.5 Compound 224 40.2 Compound 225 16.3 Compound 226 183.8 Compound 227 205.5 Compound 228 403.3 Compound 229 863.9 Compound 230 26.7 Compound 231 411.7 Compound 232 1106.2 Compound 233 190.1 Compound 234 136.4 Compound 235 26.5 Compound 236 1657.6 Compound 237 19.3 Compound 238 52.5 Compound 239 62.3 Compound 240 N/A Compound 241 110.7 Compound 242 63.3 Compound 243 71.9 Compound 244 130.8 Compound 245 11.7 Compound 246 103.4 Compound 247 13.0 Compound 248 29.8 Compound 249 536.9 Compound 250 276.2 Compound 251 38.5 Compound 252 73.5 Compound 253 550.7 Compound 254 18.1 Compound 255 346.3 Compound 256 209.4 Compound 257 442.7 Compound 258 19.3 Compound 259 101.0 Compound 260 160.7 Compound 261 11.9 Compound 262 23.7 Compound 263 691.3 Compound 264 202.6 Compound 265 19.5 Compound 266 748.6 Compound 267 588.2 Compound 268 7.3 Compound 269 126.9 Compound 270 167.7 Compound 271 228.6 Compound 272 162.2 Compound 273 248.2 Compound 274 403.2 Compound 275 241.0 Compound 276 139.9 Compound 277 954.8 Compound 278 809.5 Compound 279 97.4 Compound 280 98.7 Compound 281 86.6 Compound 282 1186.8 Compound 283 82.4 Compound 284 907.9 Compound 285 71.8 Compound 286 104.3 Compound 287 1426.5 Compound 288 33.5 Compound 289 21.5 Compound 290 10.9 Compound 291 157.2 Compound 292 143.1 Compound 293 27.3 Compound 294 238.3 Compound 295 391.0 Compound 296 46.9 Compound 297 354.1 Compound 298 1254.5 Compound 299 4991.0 Compound 300 960.8 Compound 301 66.9 Compound 302 669.3 Compound 303 565.4 Compound 304 46.4 Compound 305 1004.0 Compound 306 99.7 Compound 307 N/A Compound 308 336.5 Compound 309 132.8 Compound 310 453.9 Compound 311 1533.2 Compound 312 1528.3 Compound 313 51.8 Compound 314 2.9 Compound 315 12.7 Compound 316 41.6 Compound 317 90.5 Compound 318 9.5 Compound 319 1496.6 Compound 320 130.9 Compound 321 309.1 Compound 322 169.5 Compound 323 177.5 Compound 324 53.7 Compound 325 185.1 Compound 326 304.9 Compound 327 255.2 Compound 328 1132.7 Compound 329 749.2 Compound 330 599.6 Compound 331 22.8 Compound 332 354.1 Compound 333 219.3 Compound 334 3418.0 Compound 335 778.4 Compound 336 257.5 Compound 337 163.2 Compound 338 132.0 * * *

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Therefore, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optionally existing features, modifications, improvements and variations of the present invention disclosed herein and implemented herein may be adopted by those skilled in the art, and such modifications, improvements and variations are considered to be within the scope of the present invention. The materials, methods and examples provided herein represent preferred embodiments, are exemplary, and are not intended to be limiting of the scope of the present invention.

The invention has been described broadly and generally herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form a part of the invention. This includes the generic description of the invention with a limitation or negative limitation of removing any subject matter from that genus, regardless of whether the removed material is specifically described herein.

In addition, if features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.

It should be understood that although the present invention has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate and not limit the scope of the present invention. Other aspects, advantages and modifications within the scope of the present invention will be apparent to those skilled in the art.

Claims (91)

A compound of formula (I) or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof,

wherein: R ¹ is hydrogen; C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _3-10 cycloalkyl; a 3-10 membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered aryl group; or a 5-10 membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl group is optionally substituted by 1 to 4 R ^1A which may be the same or different, wherein each R ^1A is independently selected from halogen; cyano; nitro; oxo; C _1-4 alkyl; C _3-10 cycloalkyl; a 6-10 membered aryl group; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; and -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ), wherein each R ^1B1 , R ^1B2 and R ^1B3 are independently C _1-6 alkyl or C _3-6 cycloalkyl, wherein each R ^1A alkyl, cycloalkyl and aryl is optionally substituted with 1 to 4 R ^1C which may be the same or different, and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently C _1-6 alkyl, and wherein each R ^1B1 , R ^1B2 and R 1B3 are independently C 1-6 alkyl R ^1B3 alkyl and each R ^1B1 , R ^1B2 and R ^1B3 cycloalkyl are optionally substituted with 1 to 3 halogens; or R ¹ is -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein each C _1-6 alkyl or C _3-6 cycloalkyl is optionally substituted with 1 to 4 R ^1E which may be the same or different, wherein each R ^1E is independently selected from halogen; cyano; pendooxy; C _1-4 alkyl; C _3-10 cycloalkyl; 6 to 10 membered aryl; -OR ^1F1 ; -N(R ^1F1 )(R ^1F2 ); -C(O)N(R ^1F1 )(R ^1F2 ); and -NR ^1F1 C(O)R ^1F2 , wherein each R ^1F1 and R ^1F2 are independently C _1-6 alkyl, wherein each R ^1E alkyl, cycloalkyl and aryl are optionally substituted with 1 to 3 R ^1G which may be the same or different, and wherein each R ^1G is independently C _1-4 alkyl, C _1-4 alkoxy, halogen or cyano; R ² is hydrogen, or C _1-6 alkyl, optionally substituted with 1 to 3 substituents which may be the same or different and which are independently selected from halogen, cyano, C _1-4 alkoxy and C _3-10 cycloalkyl; or R ² is C _3-6 cycloalkyl, optionally substituted with 1 to 3 substituents which may be the same or different and which are independently selected from halogen, cyano, C _1-4 alkoxy and C _1-6 alkyl; each R ^{R 3} is independently selected from deuterium, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, -OR ^2A1 and -N(R ^2A1 )(R ^2A2 ), wherein the C _1-6 alkyl is optionally substituted with 1 to 3 substituents which are the same or different and which are independently selected from C _1-4 alkoxy and halogen, and wherein each R ^2A1 and R ^2A2 is independently hydrogen or C _1-3 alkyl which is optionally substituted with 1 to 3 halogens which are the same or different; n is 0, 1, 2, 3 or 4; R ⁴ is C _1-6 alkyl, optionally substituted with 1 to 3 substituents which are the same or different and which are independently selected from halogen, cyano, C _1-4 alkoxy, -C(O)N(R ^4A1 ) and -N(R ^4A1 )(R ^4A2 ), wherein each R R ^4A1 and R ^4A2 are independently hydrogen, C _1-6 alkyl or C _3-10 cycloalkyl; or R ⁴ is C _3-6 cycloalkyl, or a 3-6 membered heterocyclic group having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl or heterocyclic group is optionally substituted with 1 to 3 substituents which may be the same or different and which are independently selected from halogen, cyano, C _1-4 alkyl and C _1-4 alkoxy; X ¹ , X ² , X ³ and X ⁴ are each independently selected from CH and N; each Y ¹ and Y ² are independently hydrogen, deuterium, or optionally substituted with 1 to 3 substituents which may be the same or different and which are independently selected from deuterium, halogen, cyano, C _2-3 alkynyl, C _1-4 alkoxy and -C(O)NH-(C and Z is _a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy and C _3-6 cycloalkyl, wherein the C _1-4 alkyl group is optionally substituted with 1 to 3 substituents independently selected from C _1-4 alkoxy and halogen ^{; or Y 1} _and Z together with the carbon to which _they are attached form a C _3-6 cycloalkyl group; C a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the _cycloalkyl , aryl, heterocyclic group or heteroaryl group is each optionally substituted with 1 to 3 substituents independently selected from cyano, C _1-4 alkyl, C _1-4 alkoxy, C _6-10 aryl and halogen, wherein the C _1-4 alkyl group is optionally substituted with 1 to 3 substituents independently selected from C _1-4 alkoxy and halogen, and wherein the C _6-10 aryl group is optionally substituted with 1 to 3 substituents independently selected from C _{1-4 alkyl, C 1-4} alkoxy and halogen, _1-4 alkoxy and halogen substituents, and Y ² is hydrogen or deuterium. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound has formula (Ia):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ² is hydrogen. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ⁴ is a C _1-3 alkyl group substituted with 1 to 3 substituents which may be the same or different and which are independently selected from -CN and -F. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ⁴ is -CH ₃ . The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein Y ² is hydrogen. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIa):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIb):

Each R ³ may be the same or different. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIc):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IId):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIe):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIf):

Each R ³ may be the same or different. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIg):

Each R ³ may be the same or different. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIh):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIi):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIj):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIk):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIl):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIm):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIn):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the compound of formula (I) or formula (Ia) has formula (IIo):

The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is hydrogen. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, each of which is optionally substituted by 1 to 4 R ^1A which may be the same or different, wherein each R ^1A is independently selected from halogen; cyano; nitro; pendooxy; C _1-4 alkyl; C _3-10 cycloalkyl; 6 to 10 membered aryl; -N(R ^1B1 )(R 1B2 ); -OR 1B1 ; -SR 1B1 ; -C(O)N(R 1B1 )(R ^1B2 ); -NR 1B1 C(O)R 1B2 ; and -NR 1B1 C(O)N(R ^1B2 )(R 1B3 ), wherein each R ^1B1 , R 1B2 and R 1B3 are independently selected from halogen; cyano; nitro; pendooxy; C 1-4 alkyl; C 3-10 cycloalkyl; 6 to 10 membered aryl; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR 1B1 ; -C(O)N(R ^{1B1 )(R 1B2} ); -NR ^{1B1 C(O)R 1B2 ; and -NR 1B1} C(O)N(R ^1B2 )(R ^1B3 ), wherein each R ^1B1 , R ^1B2 and R ^{R 1B3} is independently C _1-6 alkyl or C _3-6 cycloalkyl, wherein each R ^1A alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 4 R ^1C which may be the same or different, and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently C _1-6 alkyl, and wherein each R ^1B1 , R ^1B2 and R ^1B3 alkyl and each R ^1B1 , R ^1B2 and R ^1B3 cycloalkyl are optionally substituted with 1 to 3 halogens. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is C _1-6 alkyl or C _2-6 alkynyl, each of which is optionally substituted by 1 to 4 R ^1A which may be the same or different, wherein each R ^1A is independently selected from halogen, cyano, C _1-4 alkoxy and C _3-6 cycloalkyl. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, hydrate, ester or isomer, wherein R ¹ is -CH ₃ , -CHF ₂ , -CF 3 ,

,

,

,

,

,

,

,

,

,

or

. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 is independently C _1-6 alkyl or C _3-6 cycloalkyl, wherein each C _1-6 alkyl or C _3-6 cycloalkyl is optionally substituted by 1 to 4 R ^1E which may be the same or different, wherein each R ^1E is independently selected from halogen; cyano; pendooxy; C _1-4 alkyl; C _3-10 cycloalkyl; 6 to 10 membered aryl; -OR ^1F1 ; -N(R ^1F1 )(R ^1F2 ); -C(O)N(R ^1F1 )(R ^1F2 ); and -NR ^1F1 C(O)R ^1F2 , wherein each R ^1F1 and R ^1F2 are independently C _1-6 alkyl, wherein each R ^1E alkyl, cycloalkyl, and aryl is optionally substituted with 1 to 3 R ^1G which may be the same or different, and wherein each R ^1G is independently C _1-4 alkyl, C _1-4 alkoxy, halogen or cyano. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each of R ^1D1 and R ^1D2 is independently -CH ₃ , -C ₂ H ₅ or -C(CH ₃ ) ₃ . The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is

or

. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is a C _3-10 cycloalkyl group optionally substituted by 1 to 4 R ^1A groups which may be the same or different, wherein each R ^1A is independently selected from halogen; cyano; oxo; nitro; C _1-4 alkyl; C _3-10 cycloalkyl; 6 to 10 membered aryl; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; and -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ), wherein each R ^1B1 , R ^1B2 and R ^1B3 is independently C wherein each R ^1A alkyl, cycloalkyl, and aryl is optionally substituted with 1 to 4 R ^1C which may be the same or different, and wherein each R ^1C is independently C _1-4 alkyl, halogen, ^cyano , -OR _1D1 or -N(R _1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently C _1-6 ^alkyl , and wherein each R ^1B1 and R ^1B2 alkyl and each R ^1B1 and R ^1B2 cycloalkyl are optionally substituted with 1 to 3 halogens. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is a C _3-10 cycloalkyl group which is optionally substituted by 1 to 4 R ^1A groups which may be the same or different, wherein each R ^{1A group} is independently selected from halogen; cyano; oxo; nitro; C _1-4 alkyl; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 and -C(O)N(R ^1B1 )(R ^1B2 ); wherein each R ^1B1 and R ^1B2 group is independently C _1-4 alkyl or C _3-6 cycloalkyl, and wherein each R ^1A C _1-4 alkyl group is optionally substituted by 1 to 3 halogen groups, wherein each R ^1B1 and R ^1B2 group and each R ^1B1 and R ^1B2- cycloalkyl is optionally substituted with 1 to 3 halogens. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is cyclopropyl or cyclobutyl, each of which is optionally substituted by 1 to 4 R ^1A which may be the same or different and are independently selected from the following: -F, -Cl, -CN, =O, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ -NH ₂ , -OCH ₃ , -NH ₂ , -NH-CH ₂ -CF ₃ ,

, -NO ₂ , cyclopropyl, and phenyl. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is cyclopropyl or cyclobutyl, each of which is optionally substituted by 1 to 4 R ^1A which may be the same or different and are independently selected from the following: -F, -Cl, -CN, =O, -CH ₃ , -CH ₂ F, -CHF _{2 , -CF 3 ,} -CH ₂ -OH, -CH ₂ -NH ₂ , -OCH ₃ , -NH ₂ , cyclopropyl and phenyl. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is

,

,

,

,

,

,

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is

,

,

,

,

,

,

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is

,

,

,

,

,

,

,

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the C _3-10 cycloalkyl group is a C _5-10 bicyclic cycloalkyl group. The compound of claim 36 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the C _5-10 bicyclic cycloalkyl group is a C _5-8 bridged bicyclic cycloalkyl group. The compound of claim 37 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the _C5-8 bridged bicyclic cycloalkyl group is a bicyclopentyl group or a bicyclooctyl group, each of which is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from the following: -F, -Cl, -CN, _-CH3 , _-CH2F , _-CHF2 , _-CF3 , -O- _CH3 and -NH-CO- _CH3 . The compound of claim 37 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is

,

,

,

,

,

,

,

,

,

or

. The compound of claim 37 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is

,

,

,

,

,

,

,

,

or

. The compound of claim 36 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the C _5-10 bicyclic cycloalkyl group is a C _5-10 spirobicyclic cycloalkyl group. The compound of claim 41 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the C _5-10 spirobicyclic cycloalkyl is spiropentyl, spirohexyl, spiroheptyl or spirodecanyl, each of which is optionally substituted with 1 to 4 R ^1A which may be the same or different, wherein each R ^1A is independently selected from -F, -Cl, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CN and -O-CH ₃ . The compound of claim 41 or its pharmaceutically acceptable salt, hydrate, ester or isomer, wherein R ¹ is

,

,

,

,

,

,

,

,

,

,

,

,

,or

. The compound of claim 41 or its pharmaceutically acceptable salt, hydrate, ester or isomer, wherein R ¹ is

,

,

,

,

,

,

,

,

,

,

,

,or

. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is a 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted by 1 to 4 R ^1A which may be the same or different, wherein each R ^1A is independently selected from halogen; cyano; oxo; nitro; C _1-4 alkyl; C _3-10 cycloalkyl; 6- to 10-membered aryl; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; and -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ), wherein each R R ^1B1 , R ^1B2 and R ^1B3 are independently C _1-6 alkyl or -C _3-6 cycloalkyl, wherein each R ^1B1 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 4 R ^1C which may be the same or different, and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently C _1-6 alkyl, wherein each R ^1B1 and R ^1B2 alkyl and each R ^1B1 and R ^1B2 cycloalkyl are optionally substituted with 1 to 3 halogens. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is a 3- to 8-membered heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is optionally substituted by 1 to 4 R ^1A which may be the same or different and are independently selected from the following: halogen, cyano, pendoxy or C _1-4 alkyl, wherein each R ^1A C _1-4 alkyl is optionally substituted by 1 to 3 R ^1C which may be the same or different, and wherein each R ^1C is independently C _1-4 alkoxy, halogen or cyano. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is azetyl, oxetyl, thietanyl, pyrrolidinyl, dioxolanyl, tetrahydropyranyl, piperidinyl or

The lino group is optionally substituted with 1 to 4 R ^1A groups which may be the same or different and are independently selected from the group consisting of -F, -Cl, -OH, -CN, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -C ₂ H ₅ , -CH ₂ -CF ₃ and -O-CH ₃ . The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is

,

,

,

,

,

,

,

,

,

,or

. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the 3- to 10-membered heterocyclic group forms a bicyclic heterocyclic group. The compound of claim 49 or its pharmaceutically acceptable salt, hydrate, ester or isomer, wherein the bicyclic heterocyclic group is a bridged bicyclic heterocyclic group. The compound of claim 50 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the bridged bicyclic heterocyclic group is an oxahertabicyclohexyl group optionally substituted with 1 to 4 R ^1A which may be the same or different, wherein each R ^1A is independently selected from -F, -Cl, -OH, -CN, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ and -O-CH ₃ . The compound of claim 44 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is

. The compound of claim 49 or its pharmaceutically acceptable salt, hydrate, ester or isomer, wherein the bicyclic heterocyclic group is a fused bicyclic heterocyclic group. The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein the fused bicyclic heterocyclic group is an oxahedralbicyclohexyl group optionally substituted with 1 to 4 R ^1A which may be the same or different, wherein each R ^1A is independently selected from -F, -Cl, -OH, -CN, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ and -O-CH ₃ . The compound of claim 54 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is

. The compound of claim 54 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is

. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, hydrate, ester or isomer, wherein the 3- to 10-membered heterocyclic group is a spirobicyclic heterocyclic group. The compound of claim 57 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein the spirobicyclic heterocyclic group is an oxahedral heptane substituted with 1 to 4 substituents which may be the same or different and are independently selected from the group consisting of -F, -Cl, -OH, -CN, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ and -O-CH ₃ . The compound of claim 58 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is

. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is a 6- to 10-membered aryl group which is optionally substituted by 1 to 4 R ^1A groups which may be the same or different, wherein each R ^1A is independently selected from halogen; cyano; oxo; nitro; C _1-4 alkyl; C _3-10 cycloalkyl; 6- to 10-membered aryl; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; and -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ), wherein each R ^1B1 , R ^1B2 and R ^1B3 is independently C _1-6 alkyl or C 3-10 cycloalkyl; wherein each R ^1A alkyl, cycloalkyl and aryl is optionally substituted with 1 to 4 R ^1C which may be the same or different, and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R _1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently C _1-6 alkyl, wherein each R ^1B1 and R ^1B2 alkyl and each R ^1B1 and R ^1B2 cycloalkyl ^are optionally substituted with 1 to 3 halogens. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is phenyl optionally substituted by 1 to 4 R ^1A which may be the same or different, wherein each R ^1A is independently selected from halogen, cyano, C _1-3 alkyl or C _1-4 alkoxy. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is phenyl optionally substituted with 1 to 3 R ^1A which may be the same or different, wherein each R ^1A is independently selected from -F, -Cl, -CN or -CH ₃ . The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted by 1 to 4 R ^1A which may be the same or different, wherein each R ^1A is independently selected from halogen; cyano; pendoxy; nitro; C _1-4 alkyl; C _3-10 cycloalkyl; 6- to 10-membered aryl; -N(R ^1B1 )(R ^1B2 ); -OR ^1B1 ; -SR ^1B1 ; -C(O)N(R ^1B1 )(R ^1B2 ); -NR ^1B1 C(O)R ^1B2 ; and -NR ^1B1 C(O)N(R ^1B2 )(R ^1B3 ), wherein each R ^1B1 R ^1B2 and R ^1B3 are independently C _1-6 alkyl or -C _3-6 cycloalkyl, wherein each R ^1A alkyl, cycloalkyl and aryl is optionally substituted with 1 to 4 R ^1C which may be the same or different, and wherein each R ^1C is independently C _1-4 alkyl, halogen, cyano, -OR ^1D1 or -N(R ^1D1 )(R ^1D2 ), wherein each R ^1D1 and R ^1D2 are independently C _1-6 alkyl, wherein each R ^1B1 and R ^1B2 alkyl and each R ^1B1 and R ^1B2 alkylcycloalkyl are optionally substituted with 1 to 3 halogens. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is imidazolyl, pyrazolyl, pyridinyl,

Azolyl, Iso

Azolyl,

Oxazolyl, pyridone, pyrimidinyl,

Benzoyl, isothiocyanate

oxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each of which is optionally substituted with 1 to 4 R ^1A which may be the same or different, wherein each R ^1A is independently selected from halogen; cyano; oxo; C _1-4 alkyl; C _3-10 cycloalkyl; -N(R ^1B1 )(R ^1B2 ); and -OR ^1B1 , wherein each R ^1B1 and R ^1B2 are independently C _1-6 alkyl, wherein each R ^1A alkyl, cycloalkyl and heterocyclic group is optionally substituted with 1 to 4 R ^1C which may be the same or different, and wherein each R ^1C is independently C _1-4 alkyl, halogen or cyano. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is imidazolyl, pyrazolyl, pyridinyl,

Azolyl, Isopropyl

Azolyl,

Oxazolyl, pyridone, pyrimidinyl,

Benzoyl, isothiocyanate

oxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each optionally substituted by 1 to 4 substituents which may be the same or different and are independently selected from the group consisting of halogen, cyano, C _1-4 alkyl or C _1-4 alkoxy. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is imidazolyl, pyrazolyl, pyridinyl,

Azolyl, Iso

Azolyl,

Oxazolyl, pyridone, pyrimidinyl,

Benzoyl, isothiocyanate

oxazolyl, pyrazolopyridinyl, imidazopyridinyl or benzimidazolyl, each optionally substituted by 1 to 3 substituents which may be the same or different and are independently selected from the following: -F, -Cl, -CN, -CH ₃ , -CHF ₂ , -CF ₃ , -OCH ₃ , -NH ₂ , -N(CH ₃ ) ₂ ,

or

. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ¹ is

,

,

,

,

,

,

,

The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein each R ³ is independently selected from deuterium, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, -OR ^2A1 and -N(R ^2A1 )(R ^2A2 ), wherein the C _1-6 alkyl is optionally substituted with 1 to 3 substituents which may be the same or different and which are independently selected from C _1-4 alkoxy and halogen, and wherein each R ^2A1 and R ^2A2 is independently hydrogen, or optionally C _1-4 alkyl substituted with 1 to 3 halogens which may be the same or different. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein each R ³ is independently selected from C _1-6 alkyl substituted with 1 to 3 substituents which may be the same or different and are independently selected from the following: halogen, cyano, C _1-4 alkoxy and C _3-10 cycloalkyl. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ³ is -CH ₃ . The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ³ is a halogen. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein R ³ is -F. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, hydrate, ester or isomer, wherein n is 0, 1 or 2. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein each of ^Y1 and ^Y2 is independently hydrogen, deuterium, or optionally C1-6 alkyl substituted with 1 to 3 substituents which may be the same or different and are independently selected from halogen, cyano, _C2-3 alkynyl, _C1-4 alkoxy and -C _{( O} )NH-( _C1-4H3-9 ). The compound of claim 74 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein _Y1 is a _C1-4 alkyl group substituted with 1 to 3 substituents which may be the same or different and are independently selected from halogen, cyano and _C1-4 alkoxy, and _Y2 is hydrogen. The compound of claim 75 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein Y ₁ is methyl substituted with 1 to 3 substituents which may be the same or different and are independently selected from -F, -Cl, -CN and -O-CH ₃ . The compound of claim 75 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein Y ₁ is -CH ₃ or -CH ₂ F. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein Z is a C _6-12 aryl group substituted with 1 to 3 substituents which may be the same or different and are independently selected from halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy and C _3-6 cycloalkyl, wherein the C _1-4 alkyl group is substituted with 1 to 3 substituents which may be the same or different and are independently selected from C _1-4 alkoxy and halogen. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein Z is phenyl substituted with 1 to 3 substituents which may be the same or different and are independently selected from halogen and C _1-4 alkyl. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein Z is a phenyl group substituted by 1 to 3 substituents which may be the same or different and are independently selected from -F and -Cl. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein Z is

The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein Z is a 5- or 6-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl group is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from halogen and C _1-4 alkyl. The compound of claim 82 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein Z is pyridyl substituted with 1 to 3 substituents which may be the same or different and are independently selected from -F, -Cl, -Br and -CH ₃ . The compound of claim 82 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein Z is

The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, wherein Y ₁ is -CH ₃ and Z is

or

. A pharmaceutical composition comprising a therapeutically effective amount of a compound as recited in any one of claims 1 to 85 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof, and a pharmaceutically acceptable formulation. The pharmaceutical composition of claim 86 further comprises another therapeutic agent. A use of a compound as claimed in any one of claims 1 to 85 or a pharmaceutically acceptable salt, hydrate, ester or isomer thereof or a pharmaceutical composition as claimed in claim 86 or 87 for the manufacture of a medicament for treating, stabilizing, or reducing the severity or progression of an LPAR1-mediated disease or condition, wherein the LPAR1-mediated disease or condition comprises pulmonary fibrosis or hepatic fibrosis. For use as in claim 88, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). The use of claim 88, wherein the LPAR1-mediated disease or condition is non-alcoholic steatohepatitis (NASH). The use of claim 90, wherein NASH comprises cirrhosis.